Treatment of Conditions that Increase in Severity and/or Occurrence During One or More Phases of the Menstrual Cycle

ABSTRACT

Methods are provided for treating a subject for a condition. In accordance with the subject methods, at least a portion of a subject&#39;s autonomic nervous system is modulated during at least one predetermined phase of the subject&#39;s menstrual cycle to alter the parasympathetic activity/sympathetic activity ratio in a manner that is effective to treat the subject for the condition. The subject methods find use in the treatment of a variety of different conditions, including various disease conditions, that increase in severity and/or occurrence during one or more phases of the menstrual cycle. Also provided are systems and kits for use in practicing the subject methods.

FIELD OF THE INVENTION

The field of this invention is the treatment of conditions associatedwith the autonomic nervous system and more specifically the treatment ofconditions through modulation of at least a portion of the autonomicnervous system during at least one predetermined phase of the menstrualcycle.

BACKGROUND OF THE INVENTION

There are a variety of conditions that can affect a female's health andwell-being. Certain conditions increase in severity and/or occurrenceduring one or more phases of a female's menstrual cycle. While theexacerbation of certain medical conditions during specific phases of themenstrual cycle has been recognized (commonly referred to as conditionsthat have catamenial variations), the mechanism underlying theassociation between exacerbation of medical conditions and certainmenstrual phases is poorly understood.

Treatment options directed to treating these types of conditions havethus far failed to be wholly satisfactory. For example, since the causesare poorly understood, such options are typically merely palliative,i.e., are designed for the relief of symptoms of the condition ratherthan being directed at the cause.

As such, there continues to be an interest in the development of newprotocol options for treating conditions that increase in severityand/or occurrence during one or more phases of a female's menstrualcycle.

SUMMARY OF THE INVENTION

Methods are provided for treating a subject for a condition. Inaccordance with the subject methods, at least a portion of a subject'sautonomic nervous system is modulated during at least one predeterminedphase of the subject's menstrual cycle to alter the parasympatheticactivity/sympathetic activity ratio in a manner that is effective totreat the subject for the condition. The subject methods find use in thetreatment of a variety of different conditions, including variousdisease conditions, that increase in severity and/or occurrence duringone or more phases of the menstrual cycle. Also provided are systems andkits for use in practicing the subject methods.

DETAILED DESCRIPTION OF THE INVENTION

Methods are provided for treating a subject for a condition. Inaccordance with the subject methods, at least a portion of a subject'sautonomic nervous system is modulated during at least one predeterminedphase of the subject's menstrual cycle to alter the parasympatheticactivity/sympathetic activity ratio in a manner that is effective totreat the subject for the condition. The subject methods find use in thetreatment of a variety of different conditions, including variousdisease conditions, that increase in severity and/or occurrence duringone or more phases of the menstrual cycle. Also provided are systems andkits for use in practicing the subject methods.

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention.

As summarized above, the subject invention provides methods for treatinga subject for a condition that has catamenial variations by modulatingat least a portion of the autonomic nervous system during at least onepredetermined phase of the menstrual cycle. The modulation may increasethe parasympathetic activity/sympathetic activity ratio or decrease theparasympathetic activity/sympathetic activity ratio. In certainembodiments, the differential between the parasympathetic activity leveland the sympathetic activity level will just be altered (increased ordecreased), but the parasympathetic activity/sympathetic activity ratiomay stay the same. In further describing the subject invention,representative embodiments of the subject methods are described first ingreater detail, followed by a review of various representativeapplications in which the subject methods may find use. Next, a reviewof systems and kits for use in the subject methods is provided.

METHODS

As noted above, the subject methods are methods for treating a femalesubject for a condition by modulating at least a portion of theautonomic nervous system during at least one predetermined phase of thesubject's menstrual cycle. Conditions include those that are at leastsuspected of increasing in severity and/or occurrence during at leastone phase of a subject's menstrual cycle and include known and to bediscovered conditions that have catamenial variations. Accordingly, thesubject methods may be employed to at least decrease the severity and/oroccurrence of such a condition at least during the one or more phases ofthe menstrual cycle in which the condition is at least suspected ofincreasing in severity and/or occurrence.

The modulation of at least a portion of the autonomic nervous systemduring at least one predetermined menstrual cycle phase may beaccomplished using any suitable method. For example, certain embodimentsmay include pharmacologically modulating and/or electrically modulating(i.e., applying electrical energy) at least a portion of the autonomicnervous system to modulate the parasympathetic activity/sympatheticactivity ratio in a manner effective to treat a female for a condition,for example to increase the parasympathetic activity/sympatheticactivity ratio or decrease the parasympathetic activity/sympatheticactivity ratio. In certain embodiments the autonomic nervous system ismodulated during at least one predetermined menstrual cycle phase toincrease the sympathetic/parasympathetic ratio.

Exacerbation of certain medical conditions during specific phases of themenstrual cycle has long been recognized. Mechanisms of the cyclicvariation are poorly understood, but are often attributed to fluctuationin reproductive hormones. However, the inventors of the subjectinvention have discovered that, in fact, variations in autonomic balanceduring the menstrual cycle, which may have evolved as adaptations forreproduction, may at least contribute partially if not completely, tocatamenial variations in conditions and are independent of hormonalvariations.

Accordingly, to address these autonomic system dependant-catamenialvariations of conditions, embodiments of the subject invention includemodulating at least a portion of a subject's autonomic nervous systemduring at least one predetermined phase of a subject's menstrual cycleto increase or decrease the parasympathetic activity/sympatheticactivity ratio in a manner effective to treat the subject for thecondition. In accordance with the subject invention, modulating at leasta portion of autonomic nervous system may be achieved by any suitablemethod, e.g., administering an effective amount of at least onepharmacological agent and/or by applying stimulatory or inhibitoryelectrical energy, in a manner to effectively treat the subject for acondition.

Modulation of a subject's autonomic nervous system may includeincreasing one or more aspects of autonomic nervous system activity inat least a portion of the autonomic nervous system and/or decreasing oneor more aspects of autonomic nervous system activity in at least aportion of the autonomic nervous system. By “modulating at least aportion of a subject's autonomic nervous system” and analogous terms ismeant altering or changing at least a portion of a subject's autonomicnervous system by suitable means to provide a change, alteration orshift in at least one component or aspect of the autonomic nervoussystem to increase or decrease the parasympathetic activity/sympatheticactivity ratio. The modulation of the autonomic nervous system mayaffect central motor output and/or nerve conduction and/or transmitterrelease and/or synaptic transmission and/or receptor activation, but inany event is a change that provides an increase or decrease in theparasympathetic activity/sympathetic activity ratio (as used herein“activity” and “function” are used interchangeably).

Embodiments of the subject methods may be employed to alter thedominance of the parasympathetic and sympathetic systems and/or may beemployed to modulate the differential between the two systems.Modulation of the autonomic nervous system may be accomplished byincreasing and/or decreasing activity in a portion of the autonomicnervous system. By “increasing activity” and analogous terms is meantthe activity in at least a portion of the autonomic nervous system maybe increased, relative to the activity level prior to employing thesubject methods, to modulate at least a portion of the autonomic nervoussystem. For example, activity in any portion of the one or more nervefibers of the parasympathetic nervous system and/or sympathetic nervoussystem may be increased or “up-regulated” to provide the desired ratioof parasympathetic activity/sympathetic activity. By “decreasingactivity” and analogous terms is meant that activity in at least aportion of autonomic nervous system is decreased or inhibited, relativeto its activity level prior to employing the subject methods, tomodulate at least a portion of the autonomic nervous system. By“decreased” or “inhibited” activity (used herein interchangeably) ismeant to include, but is not limited to, disruption, down-regulating,dampening and partial and complete blockage of function or nerveimpulses in at least a portion of the autonomic nervous system. Forexample, activity in any portion of the one or more nerve fibers of theparasympathetic nervous system and/or sympathetic nervous system may bedecreased or “down-regulated” to provide the desired ratio ofparasympathetic activity/sympathetic activity.

Embodiments of the subject invention may include pharmacologicallymodulating at least a portion of a subject's autonomic nervous system toincrease or decrease the parasympathetic activity/sympathetic activityratio in at least a portion of the autonomic nervous system in a mannereffective to treat a condition. Accordingly, embodiments of the subjectinvention may include pharmacologically increasing or decreasingparasympathetic activity in at least a portion of the autonomic nervoussystem and/or pharmacologically increasing or decreasing sympatheticactivity in at least a portion of the autonomic nervous system. In otherwords, modulating at least a portion of autonomic nervous system totreat a condition may be achieved by administering an effective amountof at least one pharmacological agent, e.g., an amount sufficient totreat the condition of interest, during at least one predetermined phaseof the menstrual cycle.

Embodiments of the subject invention may include electrically modulatingat least a portion of a subject's autonomic nervous system to increaseor decrease the parasympathetic activity/sympathetic activity ratio inat least a portion of the autonomic nervous system, in a mannereffective to treat a condition, using electrical energy. Accordingly,embodiments of the subject invention may include electrically increasingor decreasing parasympathetic activity in at least a portion of theautonomic nervous system and/or electrically increasing or decreasingsympathetic activity in at least a portion of the autonomic nervoussystem. Embodiments may include electrically ablating one or more nervefibers. In other words, modulating at least a portion of autonomicnervous system to treat a condition may be achieved by administeringelectrical energy to at least a portion of the autonomic nervous systemin an amount sufficient to treat the condition of issue, during at leastone phase of the menstrual cycle.

Accordingly, embodiments of the subject invention may include modulatingat least a portion of a subject's autonomic nervous system to achieve adesired parasympathetic activity/sympathetic activity ratio, e.g., aratio analogous to an average parasympathetic activity/sympatheticactivity ratio observed in healthy females in the same or analogousmenstrual cycle phase (e.g., of like age as the treated subject) notexperiencing the condition being treated or not experiencing anexacerbation of the condition being treated. In other words, aparasympathetic activity/sympathetic activity ratio observed in ahealthy, “like” or, i.e., analogous subject (e.g., a subject in the sameor analogous phase of the menstrual cycle with respect to theexacerbation of the subject's condition and/or not experiencing anabnormality in the autonomic nervous system). As such, an averageparasympathetic activity/sympathetic activity ratio as observed inhealthy females may be referred to as an average “normal” ratio, whereasdeviation from this average normal ratio to a degree that causes or atleast exacerbates a condition may be referred to as an “abnormal” ratio(analogous descriptors may be used to refer to activity levels specificto the sympathetic nervous system and to the parasympathetic nervoussystem).

Embodiments of the subject invention may include modulating at least aportion of a subject's autonomic nervous system to achieve a desiredparasympathetic activity/sympathetic activity ratio, wherein the desiredratio is one that is analogous to the average ratio observed in the samesubject during a menstrual cycle phase that is different from themenstrual cycle phase during which the subject's autonomic nervoussystem is modulated (i.e., a phase other than the menstrual cycle phasein which the condition being treated is exacerbated). Accordingly, asthe parasympathetic activity/sympathetic activity ratio varies duringdifferent phases of a female's menstrual cycle, a desiredparasympathetic activity/sympathetic activity ratio may be one that iscommensurate with that observed during a particular menstrual cyclephase or phases of the subject during which exacerbation of thecondition of interest is not observed. For example, if exacerbation of agiven condition is observed in the luteal phase and not in thefollicular phase, a desired parasympathetic activity/sympatheticactivity ratio may be one that is analogous to an average ratio observedduring the follicular phase. In other embodiments, if exacerbation ofthe conditions is observed during the luteal phase of a subject, adesired parasympathetic activity/sympathetic activity ratio may be onethat is analogous to an average ratio observed in females in the lutealphase, but who do not have the condition of interest or who have thecondition of interest but the condition is not exacerbated in the lutealphase. In such instances, an average parasympatheticactivity/sympathetic activity ratio observed in the same subject duringa menstrual cycle phase other than the menstrual cycle phase duringwhich modulation is performed (i.e., during which an exacerbation of acondition is observed) may be referred to as an average “normal” ratio,whereas deviation from this average normal ratio to a degree that causesor at least exacerbates a condition may be referred to as an “abnormal”ratio (analogous descriptors may be used to refer to activity levelsspecific to the sympathetic nervous system and to the parasympatheticnervous system).

Accordingly, a parasympathetic activity/sympathetic activity ratioobserved in a subject during a predetermined menstrual cycle phase inwhich a condition is exacerbated may be characterized as abnormal withrespect to (1) an average parasympathetic activity/sympathetic activityratio observed in the same subject during a menstrual cycle phase otherthan the menstrual cycle phase during which the exacerbation of acondition is observed, and/or (2) an average parasympatheticactivity/sympathetic activity ratio observed in a healthy, “like”, i.e.,analogous subject, in the same phase of the menstrual cycle as the phasein which the exacerbation of a condition is observed in the subjectand/or (3) an average parasympathetic activity/sympathetic activityratio observed in a healthy, “like”, i.e., analogous subject, in adifferent phase of the menstrual cycle from the phase in which theexacerbation of a condition is observed in the subject.

For example, a subject may experience exacerbation of, e.g., aninflammatory condition or the like during the subject's luteal phase.Accordingly, referring to the embodiment described in (1) above, anaverage ratio of parasympathetic activity/sympathetic activity observedin the subject during, e.g., the follicular phase, may be characterizedas normal wherein the deviation from this ratio as observed in thesubject during the luteal phase may be characterized as abnormal.Referring to the embodiment described in (2) above, an averageparasympathetic activity/sympathetic activity ratio observed in healthyanalogous subjects during their luteal phases may be characterized asnormal and the deviation from this ratio as observed in the subjectexperiencing the exacerbation of the condition during luteal phase maybe characterized as abnormal. Referring to the embodiment described in(3) above, an average parasympathetic activity/sympathetic activityratio observed in healthy analogous subjects during their follicularphases (for example) may be characterized as normal and the deviationfrom this ratio as observed in the subject experiencing the exacerbationof the condition during luteal phase may be characterized as abnormal.Such examples are for exemplary purposes only and in no way are intendedto limit the scope of the invention.

The inventors of the subject invention have discovered that manyconditions may be caused or at least exacerbated by areproductive-facilitating shift of the autonomic nervous system duringone or more phases of a female's menstrual cycle. For example, theinventors have discovered that a shift to a sympathetic bias (i.e., anshift to sympathetic dominance) during the luteal phase and/or earlygestation may at least contribute to the exacerbation of certainconditions in many instances. While not being limited to any particulartheory or hypothesis, in certain instances exacerbation of a conditionmay result from a shift to sympathetic bias during the luteal phasewhich promotes a transition to a more fertility-favorable immune andphysiologic state of a female for accepting and nurturing a successfulimplantation. This shift to a sympathetic bias also promotes a shift torelative T helper (Th)-2 biased immunity which may favor maternaltolerance of an embryo by attenuating Th-1 mediated interference ofimplantation. Sympathetic bias may further support gestation throughphysiological effects such as increased cardiac output and systemicvascular resistance. In such instances where a shift to sympathetic biashas occurred, e.g., during the luteal phase and/or menses phase, and acondition is exacerbated, the autonomic nervous system may be modulatedin accordance with the subject invention in a manner to achieve anincrease in the parasympathetic activity/sympathetic activity ratio,e.g., to a parasympathetic activity/sympathetic activity ratio observedin one or more other phases of the subject's menstrual cycle or to aratio analogous to one that has not shifted to sympathetic bias duringthe luteal phase. As a fertility-favorable sympathetic bias promotes ashift to T helper (Th)-2 bias, the level of Th2 in a subject may bedetermined and the result of that determination may be employed in thesubject methods, e.g., to determine whether a fertility-favorable levelof sympathetic activity is present in a subject (e.g. to determinewhether to begin and/or continue and/or terminate modulation of theautonomic system). In sum, a parasympathetic activity/sympatheticactivity ratio of a subject, e.g., analogous to a parasympatheticactivity/sympathetic activity ratio observed during one or moreparticular phases of the menstrual cycle wherein exacerbation of acondition of interest is not observed, may be provided by the subjectinvention, e.g., by modulating at least a portion of the autonomicnervous system during (including just prior to the commencement of) oneor more predetermined phases of the menstrual cycle wherein exacerbationof a condition of interest is observed.

A feature of embodiments of the subject methods is that the ratio ofparasympathetic activity to sympathetic activity is increased. By“increased ratio of parasympathetic activity to sympathetic activity”and analogous terms is meant that this ratio (characterized byparasympathetic activity/sympathetic activity) is increased in at leasta portion of the autonomic nervous system, where the increase is atleast great enough to provide the desired results, e.g., great enough totreat a given condition.

While the ratio of parasympathetic function/sympathetic function may beincreased according to embodiments of the subject invention, the netresult may be a sympathetic bias (i.e., sympathetic dominance),parasympathetic bias (i.e., parasympathetic dominance) or the activitiesof the sympathetic system and parasympathetic system may besubstantially equal (i.e., neither is dominant). By “bias” is meant thatthe particular “biased” component of the autonomic nervous system has ahigher activity level than the other component. For example, asympathetic bias refers to a higher level of sympathetic activity thanparasympathetic activity, and vice versa, where such bias may besystemic or localized. The net result of the subject methods to treat acondition may be higher or greater parasympathetic activity relative tosympathetic activity in at least the area of the autonomic systemtargeted or rather in need of modulation, higher or greater sympatheticactivity relative to parasympathetic activity in at least the area ofthe autonomic system targeted or rather in need of modulation, orsubstantially equal activity levels of parasympathetic activity andsympathetic activity.

A feature of embodiments of the subject methods is that the ratio ofparasympathetic activity to sympathetic activity is decreased. By“decreased ratio of parasympathetic activity to sympathetic activity”and analogous terms is meant that this ratio (characterized byparasympathetic activity/sympathetic activity) is decreased in at leasta portion of the autonomic nervous system, where the decrease is atleast great enough to provide the desired results, e.g., great enough totreat a given condition.

While the ratio of parasympathetic function/sympathetic function may bedecreased according to embodiments of the subject invention, the netresult may be a sympathetic bias (i.e., sympathetic dominance),parasympathetic bias (i.e., parasympathetic dominance) or the activitiesof the sympathetic system and parasympathetic system may besubstantially equal (i.e., neither is dominant).

As the subject methods include modulating at least a portion of asubject's autonomic nervous system, the modulation may be systemic orregional (i.e., localized). In other words, the entire autonomic nervoussystem may be modulated (e.g., the entire parasympathetic nervous systemand/or sympathetic nervous system may be modulated) or only a portion ofthe autonomic nervous system may be modulated (e.g., only a portion ofthe parasympathetic nervous system and/or sympathetic nervous system maybe modulated). Localization may be with respect to a particular area oreven to a particular nerve fiber. Localization may be with respect toinnervations of one or more particular organs.

Embodiments of the subject methods also include determining and/ormonitoring one or more indicators, effects or results of the autonomicnervous system. For example, the level of T helper cells (Th1 and/orTh2) may be monitored, e.g., as an indicator of a parasympatheticactivity/sympathetic activity ratio. Other indicators are described ingreater detail below, and include, but are not limited to, heart ratevariability (“HRV”), respiratory sinus arrhythmia, measures such a lowfrequency peak (“LF”), high frequency peak (“HF”), and LF/HF ratio,where such may be used as surrogates for autonomic balance. Any suitableindicator(s) may be monitored at any suitable time including before,during and after modulating the autonomic nervous system in accordancewith the subject invention.

Methods of Treating a Subject for a Condition by Increasing orDecreasing the Parasympathetic Activity/Sympathetic Activity RatioDuring at Least One Predetermined Phase of the Menstrual Cycle

As indicated above, embodiments of the subject methods include treatinga subject for a condition by modulating at least a portion of theautonomic nervous system during at least one predetermined phase of thesubject's menstrual cycle to increase or decrease the parasympatheticactivity/sympathetic activity ratio in a manner effective to treat thecondition of interest. The subject methods may be employed to treat anycondition at least suspected of being exacerbated during at least onephase of the subject's menstrual cycle. By “exacerbated” is meantbroadly to include an increase in severity and/or occurrence of thecondition.

Any area of the autonomic nervous system (any nerve of the autonomicnerve system) may be targeted according to the subject invention.Specific area(s) of the autonomic nervous system that may be modulatedwill vary, and include, but are not limited to, pre- and post ganglionicnerve fibers, ganglionic structures, efferent and afferent nerve fibers,the hypothalamus, receptors on the hypothalamus, afferent autonomicnerves (parasympathetic and sympathetic) and hormonal receptors on thehypothalamus. In certain embodiments, a given nerve fiber or the likemay be modulated with respect to parasympathetic and/or sympatheticactivity in more than one area of the nerve fiber.

The autonomic nervous system may be modulated using any suitabletechnique, including, but not limited to, surgical methods (e.g.,surgical isolation of an effector structure from parasympathetic and/orsympathetic innervation, i.e., surgically isolating an effectorstructure from one or more parasympathetic and/or sympathetic nervefibers associated with it); ablation (permanently or reversibly ablatinga nerve by employing energy delivery devices or cryotherapy);cryoablation; thermoablation; microwave energy; focus ultrasound;magnetic fields including internal and external magnetic fields; laserenergy; optical energy; radiofrequency energy; pacing mechanisms (e.g.,implantable electrode-based pacing systems, external magnetic-basedpacing system, and the like); transcutaneous electrical nervestimulation (“TENS”) or transmagentic stimulation (“TMS”) (see forexample George, M. Stimulating the Brain. Sci Amer 2003 September);pharmacological modulation; any suitable electrical modulation, and thelike. Exemplary methods using pharmacological methods and electricalenergy applying methods are now described in greater detail, where suchdescriptions are in no way intended to limit the scope of the inventionas it is to be understood that modulation of the autonomic nervoussystem may be achieved using any suitable method.

Pharmacological Modulation of at Least a Portion of the AutonomicNervous System

As described above, embodiments include treating a subject for acondition by pharmacologically modulating at least a portion of thesubject's autonomic nervous system during at least one predeterminedmenstrual phase to increase or decrease the parasympatheticactivity/sympathetic activity ratio or increase parasympathetic activityrelative to sympathetic activity. By “pharmacologically modulating atleast a portion of a subject's autonomic nervous system” is meantaltering or changing at least a portion of an autonomic nervous systemby pharmacological means (i.e., administering a pharmaceutical agent toa subject) to provide a change, alteration or shift in at least onecomponent or aspect of the autonomic nervous system. The pharmacologicalmodulation of the autonomic nervous system may affect central motoroutput and/or nerve conduction and/or transmitter release and/orsynaptic transmission and/or receptor activation, and the like, but inany event provides an increase (or decrease in certain embodiments) inthe parasympathetic activity/sympathetic activity ratio during at leastone predetermined menstrual phase.

For example, embodiments may include pharmacologically modulating atleast a portion of a subject's autonomic nervous system to alter, shiftor change the activity in at least one of the sympathetic system andparasympathetic system from a first state to a second state, where thesecond state is characterized at least by an increase in theparasympathetic activity/sympathetic activity ratio relative to thefirst state. One or more pharmacological agents may be employed toincrease and/or decrease activity in at least a portion of the autonomicnervous system. For example, embodiments may include administering oneor more pharmacological agents to achieve one or more of the following(but in any event to achieve a net result of an increase or decrease inparasympathetic activity/sympathetic activity ratio, relative to theparasympathetic activity/sympathetic activity ratio prior topharmacological modulation): (1) increasing activity in at least onesympathetic nerve fiber to achieve an increase in activity at least aportion of the sympathetic system, (2) increasing activity in at leastone parasympathetic nerve fiber to achieve an increase in activity in atleast a portion of the parasympathetic system, (3) inhibiting activityin at least one sympathetic nerve fiber to achieve a decease in activityat least a portion of the sympathetic system, and (4) inhibitingactivity in at least one parasympathetic nerve fiber to achieve adecease in activity in at least a portion of the parasympathetic system.Certain embodiments of the subject invention may include administeringan effective amount of one or more pharmacological agents to bothincrease activity in at least a portion of the autonomic nervous system,e.g., increase activity in at least one parasympathetic nerve fiber, andinhibit activity in at least a portion of the autonomic nervous system,e.g., inhibit activity in at least one sympathetic nerve fiber, to treatcondition.

Pharmacological modulation in accordance with the subject invention maybe performed prior to and/or at the same time and/or subsequent to anyother medical or clinical treatment regime such as any one or more ofthose described above, for example, electrical modulation of at least aportion of the subject's autonomic nervous system, e.g., as described incopending U.S. application Ser. No. 10/661,368, entitled “Treatment ofConditions Through Electrical Modulation of the Autonomic NervousSystem”, the disclosure of which is herein incorporated by reference,and the like. In other words, the subject methods may include otherconcomitant therapies or treatments to treat the same or differentcondition.

According to embodiments of the subject invention, pharmacologicalmodulation is accomplished by at least administering an effective amountof at least one pharmacological agent to a subject to treat the subjectfor a condition caused, precipitated or otherwise exacerbated,influenced or affected during at least one predetermined menstrualphase, to increase the parasympathetic activity/sympathetic activityratio during a given predetermined menstrual phase or phases. In otherwords, prior to practicing the subject invention, activity in at least aportion of the autonomic nervous system is at a level that is at leastcontributing to or otherwise affecting or exacerbating a condition sucha disease condition, and as such modulation of the autonomic nervoussystem may be employed to treat the condition.

That is, embodiments of the subject methods include administering aneffective amount, i.e., a therapeutically effective amount (alsoreferred to as a pharmacologically effective amount), of one or morepharmacological agents to a subject to modulate at least a portion ofthe subject's autonomic nervous system. By “effective amount” andanalogous terms is meant a dosage sufficient to modulate at least aportion of a subject's autonomic nervous system for a given period oftime. The effective amount will vary with the age and physical conditionof the subject, type and severity of the condition being treated, theduration of the treatment, the nature of any concurrent treatment, thepharmaceutically acceptable carrier used if any, and analogous factorswithin the knowledge and expertise of those skilled in the art.Introduction of an effective amount of a pharmacological agent to asubject resulting in a modulation of at least a portion of the autonomicnervous system that may be temporary or permanent.

In certain embodiments, more than one pharmacological agent may beadministered at the same or different time as another pharmacologicalagent to treat a female for the same or different condition, where thepharmacological agents administered by differ in one or more respected,e.g., may be different types of agents or may be the same typepharmacological agent but that differ in mode of administration, dosage,etc.

The effective amount of a given pharmacological agent may vary somewhatfrom subject to subject, and may depend upon factors such as, but notlimited to, the age of the subject, the health of the subject, theparticular condition being treated, the form of the pharmacologicalagent, the route and method of delivery, etc., as noted above. Suchdosages may be determined in accordance with routine pharmacologicalprocedures known to those skilled in the art. Pharmacological agentand/or adjuvants may be administered to a subject in a single oral dose,one time a day or more for days, weeks, months, years, even as long as asubject's lifetime or as long as the subject experiences the conditionof interest. For example, embodiment may include administering a givenpharmacological agent one time a day over a prolonged period of time,e.g., over a particular time period coinciding with at least a portionof one or more menstrual cycle phases (e.g., over about the second halfof the menstrual cycle, e.g., the luteal phase or at least the start ofthe luteal phase, the menses phase or at least the start of the mensesphase, and the like), e.g., over about 1 week, e.g., over about 1-3months, e.g., about 3 months to about 3 years or more, e.g., orally orwith a medical infusion pump or similar device designed for delivery ofa substance over a prolonged period.

The frequency of administration of a pharmacological agent may varydepending, e.g., on one or more of the factors described above. Forexample, the frequency of administration of a pharmacological agent mayrange from about 1 time per day to multiple times per day, e.g., about 2times or more per day or as necessary to treat or otherwise control ormanage a condition. The duration of therapy depends on the particularcondition being treated and may range from as short as about 24 hours toas long as the life of the subject. For example, at least one autonomicnervous system modulating-pharmacological agent may be delivered to asubject during one or more predetermined phases of a subject's menstrualcycle such as during about the predetermined second half of themenstrual cycle, e.g., during a predetermined luteal phase or the likeevery month for months, years or even the entire lifetime of thesubject. By “adjuvants” is meant a compound that, when used incombination with the one or more pharmacological agent compounds and/orcompositions, augments or otherwise alters or modifies the resultantpharmacological and/or physiological responses.

Embodiments may include daily discrete or continuous unit doses whereinthe total number of daily units may be equal to the total number of daysof a given predetermined phase of the menstrual cycle, the total numberof days of a month or menstrual cycle, and the like, in the form of apack. For example, embodiments may include daily discrete or continuousunit doses wherein the total number of daily units may be equal to thetotal number of days of a month or menstrual cycle, e.g., in the form ofa monthly pack. Such a monthly pack may include a plurality of unitdosage forms having the same or different dosages of a pharmacologicalagent. For example, embodiments may include a monthly pharmacologicalagent pack wherein the dosage of active agent of certain unit dosageforms of the pack to be administered to a subject during one or morepredetermined phases of the menstrual cycle (e.g., one or morepredetermined phases of the menstrual cycle wherein exacerbation of acondition is observed, e.g., the second half of the menstrual cycle,e.g., the luteal phase and/or menses phase) may differ in dosage fromone or more other unit dosage forms to be administered to the subjectduring one or more other predetermined phases of the menstrual cycle(e.g., one or more other predetermined phases of the menstrual cyclewherein exacerbation of a condition is not observed).

Depending on the particular pharmacological agent administered to asubject, the pharmacological agent may be administered to a subjectusing any convenient means capable of resulting in the desiredmodulation of the autonomic nervous system. Thus, the at least onepharmacological agent may be incorporated into a variety of formulationsfor therapeutic administration. More particularly, the pharmacologicalagent may be formulated into pharmaceutical compositions by combinationwith appropriate, pharmaceutically acceptable carriers. By“pharmaceutically acceptable carrier” is meant a component such as acarrier, diluent, excipient, and the like of a composition that iscompatible with the particular pharmacological agent and other optionalingredients of the subject pharmacological agent compositions in that apharmaceutically acceptable carrier may be combined with thepharmacological agent without eliminating the biological ortherapeutically effective activity of the pharmacological agent, and issuitable for use in subjects as provided herein without undue adverseside effects (such as toxicity, irritation, allergic response, anddeath). Side effects are “undue” when their risk outweighs the benefitprovided by the pharmacological agent. Non-limiting examples ofpharmaceutically acceptable components include, but are not limited to,any of the standard pharmaceutical carriers such as phosphate bufferedsaline solutions, water, emulsions such as oil/water emulsions orwater/oil emulsions, microemulsions, and various types of wettingagents. Accordingly, the pharmacological agent employed in the subjectmethods may be formulated into preparations in solid, semi-solid (e.g.,gel), liquid or gaseous forms, such as tablets, capsules, powders,granules, ointments, solutions, suppositories, injections, inhalants andaerosols. As such, administration of a pharmacological agent may beachieved in various ways, including, but not limited to, oral, buccal(e.g. sub-lingual), rectal, topical (including both skin and mucosalsurfaces, including airway surfaces), parenteral (e.g., subcutaneous,intramuscular, intradermal, intravenous and intrathecal),intraperiactivityal, transdermal, intratracheal, intravaginal,endocervical, intrathecal, intranasal, intravesicular, in or on the eye,in the ear canal, etc., administration. In certain embodiments, a givenpharmacological agent may be administered via a transdermal patch orfilm system such as or analogous to that described, e.g., in U.S. Pat.Nos. 6,503,532; 5,302,395; 5,262,165; 5,248,501; 5,232,702; 5,230,896;5,227,169; 5,212,199; 5,202,125; 5,173,302; 5,154,922; 5,139,786;5,122,383; 5,023,252; 4,978,532; 5,324,521; 5,306,503; 5,302,395;5,296,230; 5,286,491; 5,252,334; 5,248,501; 5,230,896; 5,227,169;5,212,199; 5,202,125; 5,173,302; 5,171,576; 5,139,786; 5,133,972;5,122,383; 5,120,546; 5,118,509; 5,077,054; 5,066,494; 5,049,387;5,028,435; 5,023,252; 5,000,956; 4,911,916; 4,898,734; 4,883,669;4,882,377; 4,840,796; 4,818,540; 4,814,173; 4,806,341; 4,789,547;4,786,277; 4,702,732; 4,690,683; 4,627,429; and 4,585,452, thedisclosures of which are herein incorporated by reference.

As noted above, embodiments may include pharmaceutical formulations fororal administration that may be formulated using pharmaceuticallyacceptable carriers well known in the art in dosages suitable for oraladministration. Such carriers enable the pharmaceutical formulations tobe formulated in unit dosage forms as tablets, pills, powder, dragees,capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc.,suitable for ingestion by the patient. Pharmaceutical preparations fororal use may be obtained through combination of at least onepharmacological agent with a solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable additional compounds, if desired, to obtain tablets or drageecores. Suitable solid excipients include, but are not limited to,carbohydrate or protein fillers and include, but are not limited tosugars, including lactose, sucrose, mannitol, or sorbitol; starch fromcorn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxypropylmethyl-cellulose or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate; with optional lubricants, such as talcor magnesium stearate; and if desired, with diluents, buffering agents,moistening agents, preservatives and flavoring agents.

Accordingly, pharmacological formulations suitable for oraladministration in accordance with the subject invention may be presentin discrete units, such as capsules, cachets, lozenges, tablets, and thelike, each containing a predetermined amount of the activepharmacological agent; as a powder or granules; as a solution or asuspension in an pharmacological formulations may be prepared by anysuitable method of pharmacy which includes, but is not limited to,bringing into association the active pharmacological agent and asuitable carrier (which may contain one or more optional ingredients asnoted above). For example, pharmacological formulations for use with thesubject invention may be prepared by uniformly and intimately admixingthe active pharmacological agent with a liquid or finely divided solidcarrier, or both, and then, if necessary, shaping the resulting mixture.For example, a tablet may be prepared by compressing or molding a powderor granules containing the active pharmacological agent, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the pharmacological agent in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent, and/or surface active/dispersingagent(s). Molded tablets may be made by molding, in a suitable machine,the powdered pharmacological agent moistened with an inert liquidbinder.

A pharmacological agent of this invention may also be administered inthe form of suppositories for rectal administration of the drug. Theseformulations may be prepared by mixing a pharmacological agent with asuitable non-irritating vehicle or excipient which is solid at ordinarytemperatures but liquid at the rectal temperatures and will thereforemelt in the rectum to release the drug. Such materials include, but arenot limited to, cocoa butter, carbowaxes and polyethylene glycols.Embodiments include a pharmacological agent made into suppositories bymixing with a variety of bases such as emulsifying bases orwater-soluble bases.

A pharmacological agent of this invention may also be administered byintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995).

For example, embodiments may also include a pharmacological agent in anaerosolized, atomized or nebulized vapor form, e.g., administrable via ametered dose device or nebulizer, and the like such that embodimentsalso include aerosolizing, vaporizing or nebulizing one or morepharmacological agents for administration to a subject. Accordingly, apharmacological agent may be utilized in aerosol formulation or ananalogous formulation to be administered via inhalation or analogousmeans. The pharmacological agent employed in the practice of the presentinvention may be formulated into pressurized acceptable propellants suchas dichlorodifluoromethane, propane, nitrogen and the like.

A pharmacological agent employed in the subject invention may bedelivered transdermally, by a topical route, formulated as applicatorsticks, solutions, suspensions, emulsions, gels, creams, ointments,pastes, jellies, paints, powders, and aerosols. For example, embodimentsmay include a pharmacological agent in the form of a discrete patch orfilm or plaster or the like adapted to remain in intimate contact withthe epidermis of the recipient for a period of time. For example, suchtransdermal patches may include a base or matrix layer, e.g., polymericlayer, in which one or more pharmacological agents are retained. Thebase or matrix layer may be operatively associated with a support orbacking. Pharmacological formulations suitable for transdermaladministration may also be delivered by iontophoresis and may take theform of an optionally buffered aqueous solution of the pharmacologicalcompound. Suitable formulations may include citrate or bis/tris buffer(pH 6) or ethanol/water and contain a suitable amount of activeingredient.

A pharmacological agent of the invention may also be delivered asmicrospheres for slow release in the body. For example, microspheres maybe administered via intradermal injection of drug-containingmicrospheres, which slowly release subcutaneously (see Rao, J. BiomaterSci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gelformulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, asmicrospheres for oral administration (see, e.g., Eyles, J. Pharm.Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routesafford constant delivery for weeks or months.

A pharmaceutical formulation of the invention may be provided as a saltand may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thatare the corresponding free base forms. In other cases, a preparation maybe a lyophilized powder that is combined with buffer prior to use.

Pharmacological formulations of the subject invention may be useful forparenteral administration, such as intravenous (“IV”) administration,intramuscular (“IM”), subcutaneous (“SC” or “SQ”), mucosal. Theformulations for administration may include a solution of thepharmacological agent dissolved in a pharmaceutically acceptablecarrier. Among the acceptable vehicles and solvents that may beemployed, include, but are not limited to, water and Ringer's solution,an isotonic sodium chloride, etc. In addition, sterile fixed oils mayconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. Accordingly, apharmacological agent may be formulated into preparations for injectionby dissolving, suspending or emulsifying them in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives. These solutions are sterile and generallyfree of undesirable matter. These formulations may be sterilized byconventional, well known sterilization techniques. The formulations maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike. The concentration of pharmacological agent in these formulationsmay vary widely, and will be selected based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the formulation may be a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a nontoxic parenterally-acceptable diluent orsolvent, such as a solution of 1,3-butanediol, and the like.Accordingly, pharmacological formulations suitable for parenteraladministration may include sterile aqueous and non-aqueous injectionsolutions of one or more active pharmacological agents, whichpreparations may be isotonic with the blood of the intended recipient.These preparations may contain, buffers and solutes which render theformulation isotonic with the blood of the intended recipient. Aqueousand non-aqueous sterile suspensions may include suspending agents andthickening agents. The formulations may be presented in single- ormulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example, saline orwater-for-injection immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the kind described above.

In other embodiments, the pharmacological formulations of the inventionmay be delivered by the use of liposomes which fuse with the cellularmembrane or are endocytosed, i.e., by employing ligands attached to theliposome, or attached directly to the oligonucleotide, that bind tosurface membrane protein receptors of the cell resulting in endocytosis.By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thepharmacological agent into the target cells in vivo. (See, e.g.,Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin.Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587,1989). Accordingly, embodiments may include a pharmacological agentadministered as liposomal formulations of the pharmacological agent.Methods for preparing liposomal suspensions are known in the art andthus will not be described herein in great detail. Briefly, in thoseembodiments where the pharmacological agent is an aqueous-solublepharmacological agent, the pharmacological agent may be incorporatedinto lipid vesicles using conventional liposome technology. In suchinstances, due to the water solubility of the pharmacological agent, thepharmacological agent may be substantially entrained within thehydrophilic center or core of the liposomes. The lipid layer employedmay be of any conventional composition and may either containcholesterol or may be cholesterol-free. When the pharmacological agentof interest is water-insoluble, the pharmacological agent may besubstantially entrained within the hydrophobic lipid bilayer which formsthe structure of the liposome employing conventional liposome formationtechnology. In either instance, the liposomes which may be produced maybe reduced in size, as through the use of standard sonication andhomogenization techniques. Embodiments of liposomal formulationscontaining the pharmacological agent of interest may be lyophilized toproduce a lyophilizate which may be reconstituted with apharmaceutically acceptable carrier, such as water, to regenerate aliposomal suspension.

Embodiments of the pharmacological agent employed in the practice of thesubject invention may include pharmaceutical compositions that may beprepared from water-insoluble compounds, or salts thereof, such asaqueous base emulsions. In such embodiments, the pharmacologicalcomposition will typically contain a sufficient amount ofpharmaceutically acceptable emulsifying agent to emulsify the desiredamount of the pharmacological agent. Useful emulsifying agents include,but are not limited to, phosphatidyl cholines, lecithin, and the like.

As noted above, in addition to active pharmacological agent, thepharmaceutical compositions of the subject invention may contain otheradditives, such as pH-adjusting additives. In particular, usefulpH-adjusting agents include acids, such as hydrochloric acid, bases orbuffers, such as sodium lactate, sodium acetate, sodium phosphate,sodium citrate, sodium borate, or sodium gluconate. Furthermore,pharmacological compositions may, though not always, contain microbialpreservatives. Microbial preservatives that may be employed include, butare not limited to, methylparaben, propylparaben, and benzyl alcohol.The microbial preservative may be employed when the pharmacologicalformulation is placed in a vial designed for multidose use.Pharmaceutical compositions for use in practicing the subject methodsmay be lyophilized using techniques well known in the art.

Pharmaceutically acceptable excipients, such as vehicles, adjuvants,carriers or diluents, that may be employed in the subject invention arereadily available to the public. Moreover, pharmaceutically acceptableauxiliary substances, such as pH adjusting and buffering agents,tonicity adjusting agents, stabilizers, wetting agents and the like, arereadily available to the public.

Embodiments may also include administration of a pharmacological agentusing a pharmacological delivery device such as, but not limited to,pumps (implantable or external devices and combinations of both (e.g.,certain components may be implantable and others may be external to thebody such as controls for the implantable components), epiduralinjectors, syringes or other injection apparatus, catheter and/orreservoir operatively associated with a catheter, etc. For example, incertain embodiments a delivery device employed to deliver a givenpharmacological agent to a subject may be a pump, syringe, catheter orreservoir operably associated with a connecting device such as acatheter, tubing, or the like. Containers suitable for delivery of apharmacological agent to a pharmacological agent administration deviceinclude instruments of containment that may be used to deliver, place,attach, and/or insert the pharmacological agent into the delivery devicefor administration of the pharmacological agent to a subject andinclude, but are not limited to, vials, ampules, tubes, capsules,bottles, syringes and bags. Embodiments may also include administrationof a pharmacological agent via a biodegradable implant drug deliverydevice. Such may be accomplished by employing syringes to deposit such abiodegradable delivery device under the skin of a subject. The implantsdegrade completely, so that removal is not necessary.

Embodiments may include employing an electrode to deliver apharmacological agent to a subject. For example, an electrode may beused that has a small port at its tip which is connected to a reservoiror pump containing a pharmacological agent. The pharmacological agentdelivery electrode may be implanted using any suitable technique such assurgical cut down, laparoscopy, endoscopy, percutaneous procedure, andthe like. In certain embodiments a reservoir or pump may also beimplanted in the subject's body. The pharmacological agent deliveryelectrode, or other analogous device, may be controllable such that theamount of pharmacological agent delivered, the rate at which thepharmacological agent may be delivered, and the time period over whichthe pharmacological agent may be delivered, etc., may be controllableand may be adjusted.

In certain embodiments, the pharmaceutically acceptable carrier may bepreservative free. By “preservative free” is meant the substantialabsence of chemical, antibacterial, antimicrobial, or antioxidativeadditives, or the like, from the pharmaceutically acceptable carriers ofthe present invention. “Substantial absence” may mean that nopreservative is present in the compositions or that trace amounts may bepresent that impart no detectable effect otherwise attributable to apreservative. For example, the pharmaceutically acceptable carrier maybe characterized by the substantial absence of chemical, antibacterial,antimicrobial, or antioxidative additives or the like (e.g., containless than about 5.0, 4.0, 3.0, 2.0, 1.0, 0.5, 0.1, 0.05, 0.01, or evenabout 0.00 percent by weight of a preservative). Further, suchformulations may be substantially or essentially free of alcohols suchas ethanol (e.g., contain less than about 5.0, 4.0, 3.0, 2.0, 1.0, 0.5,0.1, 0.05, 0.01, or even about 0.00 percent by weight of alcohols suchas ethanol). Examples of suitable pharmacological formulations include,but are not limited to, formulations that include one or more activepharmacological agents and physiological saline solution (optionallyincluding other typical ingredients such as other active agents andbuffers).

As noted above, in pharmaceutical dosage forms, a given pharmacologicalagent may be administered alone or in appropriate association with, aswell as in combination with, other pharmaceutically active compounds. Asused herein, “administered with” means that a given pharmacologicalagent and at least one other adjuvant (including one or more otherdifferent pharmacological agents) are administered at times sufficientlyclose that the results observed are indistinguishable from thoseachieved when the pharmacological agent and at least one other adjuvantare administered at the same point in time. The pharmacological agentand at least one other adjuvant may be administered simultaneously(i.e., concurrently) or sequentially. Simultaneous administration may becarried out by mixing a given pharmacological agent and at least oneother adjuvant prior to administration, or by administering a givenpharmacological agent and at least one other adjuvant at the same pointin time. Such administration may be at different anatomic sites or usingdifferent routes of administration. The phrases “concurrentadministration,” “administration in combination,” “simultaneousadministration” or “administered simultaneously” may also be usedinterchangeably and mean that a given pharmacological agent and at leastone other adjuvant are administered at the same point in time orimmediately following one another. In the latter case, thepharmacological agent and at least one other adjuvant are administeredat times sufficiently close that the results produced are synergisticand/or are indistinguishable from those achieved when the at least onepharmacological agent and at least one other adjuvant are administeredat the same point in time. Alternatively, a pharmacological agent may beadministered separately from the administration of an adjuvant, whichmay result in a synergistic effect or a separate effect. The methods andexcipients described herein are merely exemplary and are in no waylimiting.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions may be provided wherein each dosage unit, forexample, teaspoonful, tablespoonful, tablet or suppository, contains apredetermined amount of a pharmacological agent. Similarly, unit dosageforms for injection or intravenous or other suitable administrationroute may include the pharmacological agent(s) in a composition as asolution in sterile water, normal saline or another pharmaceuticallyacceptable carrier.

The term “unit dosage form,” and analogous terms as used herein refersto physically discrete units suitable as unitary dosages for human andanimal subjects, each unit containing a predetermined quantity ofpharmacological agent(s) calculated in an amount sufficient to producethe desired effect in association with a pharmaceutically acceptablediluent, carrier or vehicle. The specifications for the unit dosageforms of a given pharmacological agent employed in the practice of thepresent invention depend on, for example, the particular pharmacologicalagent employed and the effect to be achieved, the pharmacodynamicsassociated with the particular pharmacological agent in the subject,etc.

As noted above, those of skill in the art will readily appreciate thatdose levels may vary as a function of the specific pharmacologicalagent, the nature of the delivery vehicle, and the like. Dosages for agiven pharmacological agent are readily determinable by those of skillin the art by a variety of means. Exemplary dosage levels are providedherein and are not to be construed to limit the scope of the inventionin any manner.

A wide variety of different pharmacological agents may be employed inthe practice of the subject methods, where the particularpharmacological agent or combination of pharmacological agents employedwill depend on, e.g., the subject being treated, the condition beingtreated, duration of treatment, whether it is desired to increaseactivity in the parasympathetic system and/or increase activity in thesympathetic system and/or decrease activity in the sympathetic systemand/or decrease activity in the parasympathetic system, etc.

As noted above, certain embodiments include pharmacologically modulatingat least a portion of the autonomic nervous system during at least onepredetermined menstrual cycle phase of the subject to increase theparasympathetic activity/sympathetic activity ratio. Such may be thecase, for example, wherein the subject methods are employed to treatconditions such as, but not limited to: cardiovascular conditions,neurodegenerative conditions, orthopedic inflammatory conditions,inflammatory conditions, lymphoproliferative conditions, autoimmuneconditions, inflammatory conditions, infectious diseases, pulmonaryconditions, gastrointestinal conditions, endocrine conditions,genitourinary conditions, skin conditions, aging associated conditions,Th-2 dominant conditions, conditions that cause hypoxia; conditions thatcause hypercarbia; conditions that cause hypercapnia; conditions thatcause acidosis; conditions that cause acidemia; neurologic conditions,OB-GYN conditions; sudden death syndromes; menstrual related disorders;peripartum and pregnancy related disorders; fibrosis; post-operativerecovery conditions; post-procedural recovery conditions; chronic pain;trauma; bacterial infections; and fibromyalgia. Representativepharmacological agents (and analogs, derivatives and salts thereof) thatmay be used in this regard include, but are not limited to, one of moreof the following:

beta-blockers (e.g., atenolol (e.g., as sold under the brand namesTENORMIN), betaxolol (e.g., as sold under the brand name KERLONE),bisoprolol (e.g., as sold under the brand name ZEBETA), carvedilol(e.g., as sold under the brand name COREG), esmolol (e.g., as sold underthe brand name BREVIBLOC), labetalol (e.g., as sold under the brand nameNORMODYNE), metoprolol (e.g., as sold under the brand name LOPRESSOR),nadolol (e.g., as sold under the brand name CORGARD), pindolol (e.g., assold under the brand name VISKEN), propranolol (e.g., as sold under thebrand name INDERAL), sotalol (e.g., as sold under the brand nameBETAPACE), timolol (e.g., as sold under the brand name BLOCADREN),carvedilol, and the like);

aldosterone antagonists (e.g., spironolactone, eplerenone, and thelike); angiotensin II receptor blockades (e.g., candeartan (e.g.,available under the brand name ALTACAND), eprosarten mesylate (e.g.,available under the brand name TEVETAN), irbesartan (e.g., availableunder the brand name AVAPRO), losartan (e.g., available under the brandname COZAAR), etelmisartin (e.g., available under the brand nameMICARDIS), valsartan (e.g., available under the brand name DIOVAN), andthe like);

angiotensin converting enzyme (“ACE”) inhibitors (e.g., benazapril(e.g., available under the brand name LOTENSIN), captopril (e.g.,available under the brand name CAPOTEN) enalapril (e.g., available underthe brand name VASOTEC) fosinopril (e.g., available under the brand nameMONOPRIL) lisinopril (e.g., available under the brand name PRINIVIL)moexipril (e.g., available under the brand name UNIVASC) quinapril(e.g., available under the brand name ACCUPRIL) ramipril (e.g.,available under the brand name ALTACE) trandolapril (e.g., availableunder the brand name MAVIK), and the like);

statins (e.g., atorvastatin (e.g., available under the brand nameLIPITOR), cerivastatin (e.g., available under the brand name BAYCOL),fluvastatin (e.g., available under the brand name LLESCOL), lovastatin(e.g., available under the brand name MEVACOR), prevastatin (e.g.,available under the brand name PRAVACHOL), simvastatin (e.g., availableunder the brand name ZOCOR), and the like);

triglycerides lowering agents (e.g., fenofibrate (e.g., available underthe brand name TRICOR), genfibrozil (e.g., available under the brandname LOPID), and the like);

niacin;

diabetes agents (e.g., acarbose (e.g., available under the brand namePRECOSE), glimepiride (e.g., available under the brand name AMARYL),glyburide (e.g., available under the brand names MICRONASE, DIABETA),metformin (e.g., available under the brand name GLUCOPHASGE), miglitol(e.g., available under the brand name GLYCET), pioglitazone (e.g.,available under the brand name ACTOS), repaglinide (e.g., availableunder the brand name PRANDIN), rosiglitazone (e.g., available under thebrand name AVANDIA), and the like);

immunomodulators (e.g., interferon beta-1B (e.g., available under thebrand name BETASERON), interferon alfa-2A (e.g., available under thebrand name ROFERON-A) interferon alfa-2B (e.g., available under thebrand name INTRON-A), interferon alfa-2B and Ribavirin combo pack (e.g.,available under the brand name REBETRON), interferon alfa-N3 (e.g.,available under the brand name ALFERON N), interferon beta-1A (e.g.,available under the brand name AVONEX), interferon beta-1B, interferongamma immunoregulatory antibodies that bind to or react with one of thefollowing antigens: CD4, gp39, B7, CD19, CD20, CD22, CD401, CD40, CD40Land CD23, rituximab (e.g., available under the brand name RITUXAN), anychemical or radiopharmaceutical linked or conjugated antibodies thatbind to or react with one of the following antigens: CD4, gp39, B7,CD19, CD20, CD22, CD401, CD40, CD40L and CD23), and the like);

nicotine;

sympathomimetics (e.g., trimethaphan, clonidine, reserpine,guanethidine, and the like);

antihistamines (e.g., available under the brand name BENADRYL,diphenhydramine, available under the brand name ACTIFED, and the like);

cholinergics (e.g., bethanechol, oxotremorine, methacholine, cevimeline,and the like);

acetylcholinesterase inhibitors (e.g., edrophonium, neostigmine,donepezil, tacrine, echothiophate, diisopropylfluorophosphate,demecarium, pralidoxime, galanthamine, tetraethyl pyrophosphate,parathion, malathion, isoflurophate, metrifonate, physostigmine,rivastigmine, abenonium acetylchol, carbaryl acetylchol, propoxuracetylchol, aldicarb acetylchol, and the like);

magnesium and magnesium sulfates;

calcium channel blockers (e.g., amlodipine besylate (e.g., availableunder the brand name NORVASC), diltiazem hydrochloride (e.g., availableunder the brand names CARDIZEM CD, CARDIZEM SR, DILACOR XR, TIAZAC),felodipine plendil isradipine (e.g., available under the brand namesDYNACIRC, DYNACIRC CR), nicardipine (e.g., available under the brandname CARDENE SR), nifedipine (e.g., available under the brand namesADALAT CC, PROCARDIA XL), nisoldipine sulfur (e.g., available under thebrand name SULAR), verapamil hydrochloride (e.g., available under thebrand names CALAN SR, COVERA HS, ISOPTIN SR, VERELAN) and the like);

muscarinics (e.g., muscarine, pilocarpine, and the like);

sodium channel blockers, (e.g., moricizine, propafenone, encainide,flecaimide, tocainide, mexiletine, phenytoin, lidocaine, diisopyramide,quinidine, procainamide, and the like);

glucocorticoid receptor blockers (e.g., mifepristone, and the like);

peripheral adrenergic inhibitors (e.g., guanadrel (e.g., available underthe brand name HYLOREL), guanethidine monosulfate (e.g., available underthe brand name ISMELIN), reserpine (e.g., available under the brandnames SERPASIL, MECAMYLAMINE, HEXEMETHONIUM), and the like);

blood vessel dilators (e.g., hydralazine hydrochloride (e.g., availableunder the brand name APRESOLINE), minoxidil (e.g., e.g., available underthe brand name LONITEN), and the like);

central agonists (e.g., alpha methyldopa (e.g., available under thebrand name ALDOMET), clonidine hydrochloride (e.g., available under thebrand name CATAPRES), guanabenz acetate (e.g., available under the brandname WYTENSIN), guanfacine hydrochloride (e.g., available under thebrand name TENEX), and the like;

combined alpha and beta-blockers (e.g., carvedilol (e.g., availableunder the brand name COREG), labetalol hydrochloride (e.g., availableunder the brand names NORMODYNE, TRANDATE), and the like);

alpha blockers (e.g., doxazocin mesylate (e.g., available under thebrand name CARDURA), prazosin hydrochloride (e.g., available under thebrand name MINIPRESS), terazosin hydrochloride (e.g., available underthe brand name HYTRIN), and the like);

combination diuretics (e.g., amiloride hydrochloride+hydrochlorothiazide(e.g., available under the brand name MODURETIC),spironolactone+hydrochlorothiazide (e.g., Aldactazide),triamterene+hydrochlorothiazide (e.g., available under the brand namesDYAZIDE, MAXZIDE) and the like); potassium sparing diuretics (e.g.,amiloride hydrochloride (e.g., available under the brand name MIDAMAR),spironolactone (e.g., available under the brand name ALDACTONE),triamterene (e.g., available under the brand name DYRENIUM), and thelike); nitrates (e.g., L-arginine, (e.g., available under the brandnames NITROGLYCERIN DEPONIT, MINITRAN, NITROPAR, NITROCINE, NITRO-DERM,NITRO DISC, NITRO-DUR, NITROGARD, NITROGLYCERIN, NITROGLYCERIN T/R,NITRO-TIME, NITROL OINTMENT, NITROLINGUAL SPRAY, NITRONG, NITRO-BID,NITROPRESS, NITROPREX, NITRO S.A., NITROSPAN, NITROSTAT, NITRO-TRANSSYSTEM, NITRO-TRANSDERMAL, NITRO-TIME, TRANSDERM-NITRO, TRIDIL.PENTAERYTHRITOL TETRANITRATE PERITRATE, PERITRATE S.A. ErythritylTetranitrate Cardilate Isosorbide DINITRATE/PHENOBARBITAL ISORDIL W/PBISOSORBIDE MONONITRATE IMDUR, ISMO, ISOSORBIDE MONONITRATE, MONOKETISOSORBIDE NITRATE DILATRATE-SR, ISO-BID, ISORDIL, ISORDIL TEMBIDS,ISORDIL DINITRATE, ISORDIL DINITRATE LA, SORBITRATE, SORBITRATE SA), andthe like);

cyclic nucleotide monophosphodiesterase (“PDE”) inhibitors (e.g.,vardenafil (e.g., available under the brand name LEVITRA), sildenafil(e.g., available under the brand name VIAGRA) tadalafil (e.g., availableunder the brand name CIALIS) and the like);

alcohols;

vasopressin inhibitors (e.g., atosiban (Tractocile), AVP V1a (OPC-21268,SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985(Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087(Conivaptan), JTV-605, CL-385004) receptor antagonists, and the like);

oxytocin inhibitors (e.g., terbutaline, ritodrine, and the like);

glucagons like peptide 1;

relaxin hormone;

renin inhibitors (e.g., Aliskiren, and the like);

estrogen and estrogen analogues (e.g., estradiols, and the like) andmetabolites;

progesterone inhibitors;

testosterone inhibitors;

gonadotropin-releasing hormone analogues (GnRH-As);

gonadotropin-releasing hormone inhibitors (e.g., Leuprolide Acetate, andthe like);

vesicular monoamine transport (VMAT) inhibitors (e.g., tetrabenazine,and the like); dipeptidyl peptidase (DP) IV inhibitors (DP4 inhibitors)(e.g., LAF237, P93/01, P32/98, valine pyrrolidide, and the like);

melatonin; and the like;

anti-coagulants (e.g., ximelagatran (EXANTA); hirulog (BIVALIRIDIN);abciximab (REOPRO); dipridamole (AGGRENOX); anagrlide (AGRILYN);clopiogrel (PLAVIX); dipridamole (PERSANTINE); eptifibatide(INTEGRILIN); ticlopidine (TICLID); tirofibam (AGGRASTAT); ardeparin(NORMIFLO); dalteparin (FRAGMIN); dnaparoid (ORGARIN); enoxaparin(LOVENOX); lepirudin (REFLUDAN); heparin; warfarin; alteplase(ACTIVASE), t-PA); reteplase (RETEVASE); streptokinase; urokinase;aminocaproic acid (AMICAR); cilostazol (PLETAL); pentoxifylline(TRENTAL); and the like).

As noted above, one or more of the above-described a pharmacologicalagents may be employed in the practice of the subject methods and may beof particular use in modulating at least a portion of a subject'sautonomic nervous system to increase the parasympatheticactivity/sympathetic activity ratio. However, the subject methods arenot limited to the above-described active agents as otherpharmacological agents may be employed in the practice of the subjectmethods. For example, the below-described pharmacological agents may beemployed in the practice of the subject methods, where one or more ofthe following pharmacological agents may be of particular use inmodulating at least a portion of a subject's autonomic nervous system todecrease the parasympathetic activity/sympathetic activity ratio. Suchmay be the case, for example, wherein the subject methods are employedto treat certain bacterial infections, e.g., bacterial vaginosis, etc.Other conditions that may be treated by decreasing the parasympatheticactivity/sympathetic activity ratio include, but are not limited to:infertility, early pregnancy loss, spontaneous abortion, subfertility,failure of implantation, amenorrhea, luteal insufficiency, dysmenorrhea,pelvic pain, depression, bipolar disorder, bacterial vaginosis, obesity,multiple sclerosis, and the like.

Representative pharmacological agents (and analogs, derivatives andsalts thereof) that may be employed in the practice of the subjectmethods (e.g., to modulating at least a portion of a subject's autonomicnervous system during at least one predetermined menstrual cycle phaseof the subject to increase the sympathetic activity/parasympatheticactivity ratio) include, but are not limited to, one of more of thefollowing:

beta agonists (e.g., dobutamine, metaproterenol, terbutaline, ritodrine,albuterol, and the like);

alpha agonists (e.g., selective alpha 1-adrenergic blocking agents suchas phenylephrine, metaraminol, methoxamine; prednisone and steroids andthe like, (e.g., available under the brand names CORATN, DELTASONE,LIQUID PRED, MEDICORTEN, ORASONE, PANASOL-S, PREDNICEN-M, PREDNISONEINTENSOL));

indirect agents that include norepinephrine (e.g., ephedrine,amphetamines, phenylpropanolamines, cyclopentamines, tuaminoheptanes,naphazolines, tetrahydrozolines, and the like);

epinephrine and the like;

norepinephrine and the like;

acetylcholine and the like;

sodium and the like;

calcium and the like;

angiotensin I and the like;

angiotensin II and the like;

angiotensin converting enzyme I (“ACE I”) and the like;

angiotensin converting enzyme II (“ACE II”) and the like;

aldosterone and the like;

potassium channel blockers and magnesium channel blockers (e.g.,valproate (sodium valproate, valproic acid), lithium, and the like);

cocaine and the like;

amphetamines and the like;

ephedrine and the like;

terbutaline and the like;

dopamine and the like;

dobutamine and the like;

antidiuretic hormone (“ADH”) (also known as vasopressin) and the like;

oxytocin (including PITOCINE) and the like; and

THC cannabinoids.

As noted above, a combination of two or more of any of the above notedagents or like agents may be employed.

As noted above, certain embodiments may include administering apharmacologically effective amount of a first pharmacological agent anda pharmacologically effective amount of at least a second, differentpharmacological agent, e.g., concurrently administered, where the twomay differ in one or more of a variety of aspects, e.g., dosage, type,route of administration, etc. For example, embodiments may includeadministering a first type of pharmacological agent and at least oneother type of pharmacological agent to provide an enhanced therapeuticeffect. By “enhanced therapeutic effect” is meant that at least theinitial relief of the particular condition being treated by the firstpharmacological agent employed occurs more quickly with a combination ofthe first pharmacological agent and at least one other differentpharmacological agent, as compared to the same doses of each componentgiven alone, or that doses of one or all component(s) are below whatwould otherwise be a minimum effective dose (a “sub-MED”).

Accordingly, embodiments of the subject invention includes treating asubject for a condition by modulating at least a portion of thesubject's autonomic nervous system by administering a firstpharmacological agent together with at least one other, differentpharmacological agent. The pharmacological agents may be concomitantlyadministered as described above, i.e., they may be given in close enoughtemporal proximity to allow their individual therapeutic effects tooverlap. For example, embodiments of the subject invention may includethe co-timely administration of a first pharmacological agent and atleast a second, different pharmacological agent. By “co-timely” withrespect to drug administration is meant administration of a secondpharmacological agent for the treatment of a condition while a firstpharmacological agent is still present in a subject's system at atherapeutically effective amount. It is to be understood that in someinstances this will require sequential administration. Alternatively,multiple routes of administration may be employed, e.g., intravenous orsubcutaneous injection of a first pharmacological agent may be combinedwith oral administration of a second, different pharmacological agent.

Embodiments may also include pharmaceutical compositions in unit dosageforms that are useful in treating conditions by modulating at least aportion of a subject's autonomic nervous system and which contain afirst pharmacological agent and at least a second, different type ofpharmacological agent. In other words, a single drug administrationentity or single unit dosage form may include two or morepharmacological agents. For example, a single tablet, solution, capsule,dragee, trocheem suppository, syringe, transdermal patch, and the like,combining two or more pharmacological agents would be a unit dosageform. The therapeutic agents present in a unit dosage form may bepresent in amounts such that, upon administration of one or more unitdoses of the composition, a subject may experience a longer lastingefficacy than with the administration of either agent alone. Suchcompositions may be included as part of a therapeutic package in whichone or more unit doses are placed in a finished pharmaceuticalcontainer. Labeling may be included to provide directions for using thecomposition in the treatment of a condition by modulating at least aportion of a subject's autonomic nervous system. The actual amounts ofeach agent in such compositions will vary according to the specificcompositions being utilized, the particular compositions formulated, themode of application, the particular route of administration, and thelike. Dosages for a given subject can be determined using conventionalconsiderations, e.g., by customary comparison of the differentialactivities of the subject compositions and of a known agent, or by meansof an appropriate, conventional pharmacological protocol. A person ofordinary skill in the art will be able without undue experimentation,having regard to that skill and this disclosure, to determine atherapeutically effective amount of a particular pharmacological agentfor practice of this invention. For example, embodiments may includedosages conventionally administered for the particular pharmacologicalagents employed, where such dosages are known in the art.

Accordingly, in practicing the subject methods, an effective amount of apharmacological agent is administered to a subject during at least onepredetermined phase of the subject's menstrual cycle to treat acondition affecting the subject. As noted above, the particular dosage,mode of administration, treatment times, etc., will vary according to avariety of factors, but will generally fall within the rangesconventionally administered for the particular pharmacological agentemployed. As noted above, the dose of pharmacological agent will bedifferent for different subject, condition(s) treated, etc. Embodimentsinclude determining the particular condition experienced by the subjectand determining the appropriate pharmacological treatment regimenincluding dosage of particular agent(s) required to modulate at least aportion of the subject's autonomic nervous system in a manner effectiveto treat that subject for the particular condition.

The following descriptions of exemplary embodiments describe averagedoses and may vary. Such descriptions are for exemplary purposes onlyand are in no way intended to limit the scope of the invention. Forexample, the number of capsules or tablets, teaspoonfuls of solution,and the like, administered depends at least in part on the strength ofthe particular pharmacological agent administered. Furthermore, thenumber of doses administered each day, the time allowed between doses,and the length of time a subject takes the medicine, etc., depend on thecondition being treated, i.e., the condition for which a subject istaking the pharmacological agent. Exemplary treatment protocols are nowprovided. The dose of pharmacological agent may be different fordifferent subject, condition treated, etc. The following embodimentsdescribe average doses and may vary. Such are for exemplary purposesonly and are in no way intended to limit the scope of the invention. Forexample, the number of capsules or tablets, teaspoonfuls of solution,and the like, administered depends at least in part on the strength ofthe particular beta-blocker administered. Furthermore, the number ofdoses administered each day, the time allowed between doses, and thelength of time a subject takes the medicine, etc., depend on thecondition being treated, etc.

Beta-Blocker

As noted above, embodiments may include administering an effectiveamount of a beta-blocker to treat a condition. Such embodiments mayinclude administering adult oral dosage forms (capsules and tablets) ofacebutolol ranging from about 200 milligrams (mgs.) to about 1200 mgs.,e.g., from about 200 mgs. to about 800 mgs. Such oral dosages may beadministered as a single dose one time a day, two times a day, ordivided into two daily doses for an adult, etc.

Embodiments may include administering atenolol to treat a condition.Such embodiments may include administering adult oral dosage forms(e.g., tablets) of atenolol (e.g., available under the brand nameTENORMIN) that range from about 25 mgs. to about 100 mgs. once a day.For example, administration may include about 50 mgs. once a day, orabout 100 mgs. of atenolol once a day, or about 50 mgs. atenolol twotimes a day, e.g., for about six to about nine days. Embodiments thatinclude administering atenolol in adult injection dosage forms mayinclude about 5 mgs. given over 5 minutes, repeated ten minutes later.Atenolol may also be administered intravenously in certain embodiments.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of betaxolol to treat a condition. Such embodiments may includeadministering about 10 mgs. of betaxolol as an adult dosage form once aday.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of bisoprolol (e.g., available under the brand name ZEBETA) totreat a condition. Such embodiments may include administering about 5mgs. to about 10 mgs. of bisoprolol as an adult oral dosage forms (e.g.,tablets) once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of carteolol to treat a condition. Adult oral dosage forms(e.g., tablets) of carteolol may include about 0.5 mgs. to about 10 mgs.administered once a day.

Embodiments may include administering esmolol to treat a condition viaIV. esmolol may be administered via iv as follows: loading dose of about20-30 mg ivp over 1 minute using a 10 mg/ml 10 ml vial and maintenancedose of about 2 To 12 mg/min as titrated to patient response andmaintenance infusions may be increased by about 2 to 3 mg/min at 10minute intervals until the desired response is achieved.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of labetalol to treat a condition. Adult oral dosage forms(e.g., tablets) of labetalol may include about 100 mgs. to about 400mgs. two times a day. Adult injection dosage forms may include about 20mgs., e.g., injected slowly over about two minutes with additionalinjections of about 40 mgs. and about 80 mgs. given about every tenminutes if needed, up to a total of about 300 mgs., instead as aninfusion at a rate of about 2 mgs. per minute to a total dose of about50 mgs. to about 300 mgs.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of metoprolol to treat a condition. Adult oral dosage forms(e.g., tablets) of metoprolol may include about 100 mgs. to 450 mgs. aday, taken as a single dose or in divided doses. For example,embodiments may include administering about 50 mgs. about every sixhours for about 24 hours or more and then about 100 mgs. two times a dayfor about 1 to about 3 months or more, e.g., from about 1 to about 3years or more. Embodiments may include administering long-acting adultoral dosage forms (extended-release tablets) that may include up toabout 400 mgs. once a day. Adult injection dosage forms may includeabout 5 mgs. every two minutes for about three doses.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of nadolol (e.g., available under the brand name CORGARD) totreat a condition. Embodiments may include administering adult oraldosage forms (e.g., tablets) of nadolol that may include about 40 mgs.to about 320 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of oxprenolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of oxprenolol(short-acting) that may include about 20 mgs. three times a day.Embodiments may include administering adult long-acting oral dosageforms (extended-release tablets) that may include about 120 mgs. toabout 320 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of pentbutolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of pentbutololthat may include about 20 mgs. once a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of pindolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of pindolol thatmay include about 5 mgs. two times a day—up to about 60 mgs. a day.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of propranolol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of propranololthat may include, for regular (short-acting) oral dosage forms (tabletsand oral solution), about 80 mgs. to about 320 mgs. a day taken in two,three, or four divided doses up to about 640 mgs./day in certainembodiments. Embodiments may also include about 10 mgs. to about 40 mgs.three or four times a day for an adult and about 500 micrograms (0.5mgs.) to about 4 mgs. per kilogram of body weight a day taken in divideddoses for children. Embodiments may include administering long-actingadult oral dosage forms (extended-release capsules) that may includeabout 80 mgs. to about 320 mgs. once a day up to about 640 mgs. once aday. Embodiments may include administering adult injection dosage formsthat range from about 1 mg. to about 3 mgs. given at a rate not greaterthan about 1 mg per minute. The dose may be repeated after about twominutes and again after about four hours if needed. Children may beadministered about 10 mgs. to about 100 micrograms (0.01 to 0.1 mg) perkilogram of body weight given intravenously about every six to eighthours.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of sotalol to treat a condition. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of sotalol thatmay include about 80 mgs. two times a day up to about 320 mgs. per daytaken in two or three divided doses.

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of timolol (e.g., available under the brand name BLOCADREN) totreat a condition. Embodiments may include administering adult oraldosage forms' (e.g., tablets) of timolol that may include about 10 mgs.two times a day up to about 60 mgs. per day taken as a single dose or individed doses. For example, up to 30 mgs. once a day or in divideddoses.

Aldosterone Antagonists

Embodiments may include administering an aldosterone antagonist to treata condition in accordance with the subject invention. For example,embodiments may include administering adult oral dosage forms (e.g.,tablets) of spironolactone that may range from about 50 mgs. to about400 mgs. daily. Embodiments may include administering adult oral dosageforms (e.g., tablets) of eplerenone that may range from about 50 mgs. toabout 100 mgs. daily.

Angiotensin II Receptor Blockades

Embodiments may include administering an angiotensin II receptorblockade to treat a condition in accordance with the subject invention.Such embodiments may include administering an adult oral dosage form ofcandesartan (e.g., ATACAND) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 2 mgs. to about 32mgs. of candesarten daily (i.e., for a 24 hour interval), e.g., about 16mgs. daily. Embodiments may include administering adult oral dosageforms of irbersarten (e.g., AVAPRO) to a subject to treat a condition.Exemplary treatment protocols may include administering about 75 mgs. toabout 100 mgs. or more, e.g., up to about 300 mgs., of irbersartendaily. Embodiments may include administering adult oral dosage forms oflosartan (e.g., COZAAR) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 25 mgs. to about 50mgs. or more, e.g., 100 milligrams, of losarten orally once daily ortwice daily. Embodiments may include administering adult oral dosageforms of telmisartin (e.g., MICARDIS) to a subject to treat a condition.Exemplary treatment protocols may include administering about 20 mgs. toabout 80 mgs. of telmisartin daily. Embodiments may includeadministering adult oral dosage forms of valsartan (e.g., DIOVAN) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 20 mgs. to about 80 mgs. of valsarten once daily.Embodiments may include administering adult oral dosage forms ofeprosarten (e.g., TEVETAN) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 400 mgs. to about800 mgs. of eprosarten once daily or twice daily.

Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)

Embodiments may include administering an ACE inhibitor to a subject totreat a condition in accordance with the subject invention. Such mayinclude administering adult oral dosage forms of captropil (e.g.,CAPOTEN) to a subject to treat a condition. Exemplary treatmentprotocols may include administering about 12.5 mgs. to about 50 mgs. ofcaptropil over about 8 to about 12 hours. Embodiments may includeadministering adult oral dosage forms of enalapril (e.g., VASOTEC) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 5 mgs. to about 20 mgs. of enalapril once daily.Embodiments may include administering adult oral dosage forms offosinopril (e.g., MONOPRIL) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 10 mgs. to about 80mgs., e.g., about 20 mgs. to about 40 mgs., of fosinopril daily.Embodiments may include administering adult oral dosage forms oflisinopril (e.g., PRINIVIL) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 10 mgs. to about 80mgs., e.g., about 20 mgs. to about 40 mgs., of lisinopril daily.Embodiments may include administering adult oral dosage forms ofmoexipril (e.g., UNIVASC) to a subject to treat a condition. Exemplarytreatment protocols may include administering about 3.75 mgs. to about15 mgs., e.g., 7.5 mgs. of moexipril daily. Embodiments may includeadministering-adult oral dosage forms of quinapril (e.g., ACCUPRIL) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 10 mgs. to about 80 mgs, e.g., about 20 mgs., ofquinapril once daily. Embodiments may include administering adult oraldosage forms of ramipril (e.g., ALTACE) to a subject to treat acondition. Exemplary treatment protocols may include administering about2.5 mgs. to about 20 mgs. of ramipril daily. Embodiments may includeadministering adult oral dosage forms of trandolapril (e.g., MAVIK) to asubject to treat a condition. Exemplary treatment protocols may includeadministering about 1 mg. to about 4 mgs., e.g., about 2 mgs., oftrandolapril daily.

Statins

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of a statin to treat a condition in accordance with the subjectinvention. For example, embodiments may include administering adult oraldosage forms (e.g., tablets) of atorvastatin (e.g., available under thebrand name Lipitor) that may range from about 0.5 mgs. to about 80 mgs.daily. Embodiments may include administering adult oral dosage forms(e.g., tablets) of cerivastatin (e.g., available under the brand nameBaycol) that may range from about 0.2 mgs. to about 0.3 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of fluvastatin (e.g., available under the brand name lescoL)that may range from about 20 mgs. to about 80 mgs. daily. Embodimentsmay include administering adult oral dosage forms (e.g., tablets) oflovastatin (e.g., available under the brand name Mevacor) that may rangefrom about 10 mgs. to about 80 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of prevastatin(e.g., available under the brand name Pravachol) that may range fromabout 10 mgs. to about 40 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of simvastatin(e.g., available under the brand name Zocor) that may range from about 5mgs. to about 40 mgs. daily.

Triglycerides Lowering Drugs

Embodiments may include administering adult oral dosage forms (e.g.,tablets) of a triglycerides lowering drug to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering adult oral dosage forms (e.g., tablets) offenofibrate (e.g., available under the brand name TRICOR) that may rangefrom about 65 mgs. to about 200 mgs. daily. Embodiments may includeadministering adult oral dosage forms (e.g., tablets) of genfibrozil(e.g., available under the brand name LOPED) that may range from about1200 mgs. total given as about 600 mgs. two times per day (e.g., every12 hours).

Niacin

Embodiments may include administering niacin to treat a condition inaccordance with the subject invention. For example, dosing may includeadministering by mouth about 2 mgs. to about 6 mgs. total, e.g., asgiven as about 1 mg. to about 2 mgs. twice per day or three times perday.

Diabetes Agents

Embodiments may include administering a diabetes drug to treat acondition in accordance with the subject invention. For example,embodiments may include administering adult oral dosage forms (e.g.,tablets) of acarbose (e.g., available under the brand name PRECOSE) thatmay range from about 25 mgs. to about 300 mgs. for an eight hourinterval. Embodiments may include administering adult oral dosage forms(e.g., tablets) of glimepiride (e.g., available under the brand nameAMARYL) that may range from about 1 mg. to about 2 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of glyburide (e.g., available under the brand names MICRONASE,DIABETA) that may range from about 1.5 mgs. to about 5 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of metformin (e.g., available under the brand name GLUCOPHASGE)that may range from about 500 mgs. to about 850 mgs. for an 8 to 24 hourinterval. Embodiments may include administering adult oral dosage forms(e.g., tablets) of miglitol (e.g., available under the brand nameGLYCET) that may range from about 25 mgs. to about 100 mgs. for an 8hour interval. Embodiments may include administering adult oral dosageforms (e.g., tablets) of pioglitazone (e.g., available under the brandname ACTOS) that may range from about 15 mgs. to about 40 mgs. daily.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of repaglinide (e.g., available under the brand name PRANDIN)that may range from about 0.5 mgs. to about 4.0 mgs. 3 times per day.Embodiments may include administering adult oral dosage forms (e.g.,tablets) of rosiglitazone (e.g., available under the brand name AVANDIA)that may range from about 4 mgs. to about 8 mgs. daily.

Immunomodulators

Embodiments may include administering an immunomodulator to treat acondition in accordance with the subject invention. For example,embodiments may include administering interferon beta-1B (e.g.,available under the brand name BETASERON), where dosing may includeadministering about 0.25 mg. subcutaneously every other day. Embodimentsmay also include administering interferon alfa-2A (e.g., available underthe brand name ROFERON-A), where dosing may include administering about3 million units to about 36 million units per day B4/SC to about 3million units to about 36 million units 3 times per week (3 millionunits (1 ml); 6 million units/ml (3 ml); 0 million units/ml (0.9 ml), 3ml); 36 million units/ml (1 ml)). Embodiments may also includeadministering interferon alfa-2B (e.g., available under the brand nameINTRON-A), where dosing may include administering about 1 to about 30million units/M2 IM/SC three times per week (3 million units (0.5 ml); 5million units (0.5 ml); 10 million units (1 ml); 25 million units powderfor injection: 18 million units and 50 million units). Embodiments mayalso include administering interferon alfa-2B and ribavirin combinationpack (e.g., available under the brand name REBETRON), where dosing mayinclude administering INTRON A at about 3 million units subcutaneouslythree times per week and about 500 mgs. to about 600 mgs. of ribavirintwice daily. Embodiments may also include administering interferonalfa-N3 (e.g., available under the brand name ALFERON N), where dosingmay include administering about 250,000 units (0.05 ml) twice weekly (5million units (1 ml)). Embodiments may also include administeringinterferon beta-1A (e.g., available under the brand name AVONEX), wheredosing may include administering about 30 micrograms IM once weekly(reconstitute with 1.1 ml of diluent).

Nicotine

Embodiments may include administering nicotine to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering nicotine in the form of chewing gum, e.g., fromabout 2 mgs. to about 4 mgs. dosage strength). Embodiments may includeadministering nicotine as an inhalant (e.g., about 4 mgs. percartridge), nasal spray (e.g., each actuation of nicotine nasal spraymay deliver about 0.5 mgs. nicotine), or as a transdermal system. Forexample, dosing schedules (mg/day) of nicotine transdermal systems mayinclude a patch duration of about 24 hours and dosing schedule of about7 mgs. to about 22 mgs. for about 2 to about 6 weeks; a patch durationof about 16 hours and a dosing schedule of about 15 mgs. for about 4 toabout 12 weeks. Each dosing schedule may be followed by a reduced dosingschedule.

Sympathomimetics

Embodiments may include administering a sympathomimetic to treat acondition in accordance with the subject invention. For example,embodiments may include administering trimethaphan via an I.V., e.g.,about 0.1 mgs. to about 1.0 mgs./minute, up to about 15 mgs. per minute.Embodiments may include administering by mouth clonidine at about 0.1mgs. to about 2.4 mgs. daily. Embodiments may include administering bymouth reserpine at about 10 mgs. to about 20 mgs. daily. Embodiments mayinclude administering by mouth guanethidine at about 10 mgs. to about 50mgs. daily.

Antihistamines

Embodiments may include administering adult oral dosage forms of anantihistamine to treat a condition in accordance with the subjectinvention. For example, embodiments may include administering adultoral-dosage forms (e.g., tablets) of BENADRYL at about 25 mgs. to about50 mgs. three to four times daily. Nighttime dosage may include about 50mgs. at bedtime.

Cholinergics

Embodiments may include administering a cholinergic to treat a conditionin accordance with the subject invention. For example, embodiments mayinclude administering bethanechol by mouth at about 10 mgs. to about 50mgs. four times per day or three times per day. Embodiments may includeadministering methacholine as an inhaled aerosol at about 0.02 to about25.0 mg/mL. Embodiments may include orally administering about 30 mgs.cevimeline three times per day.

Acetylcholinesterase Inhibitors

Embodiments may include administering an acetylcholinesterase inhibitorto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 0.1 ml. to about0.8 ml via an I.V. edrophonium or about 1 ml. of a 1:20000 solution (0.5mg.) of neostigmine intramuscularly (IM) or subcutaneously (SC).Embodiments may also include orally administering about 5 mg ofdonepezil to about 10 mgs./day. Embodiments may also includeadministering about 1 to about 2 g of pralidoxime, e.g., as an infusionin 100 mL of saline, over about a 15 to 30 minute period, via I.V. About16 mgs to about 32 mgs. of galanthamine may be administered orally twiceper day. Physostigmine may be administered intravenously orintramuscularly e.g., about 0.5 mgs. to about 2 mgs. Rivastigmine may beorally administered, e.g., about 3 mgs. to about 6 mgs. two times perday.

Magnesium and Magnesium Sulfates

Embodiments may include administering magnesium to treat a condition inaccordance with the subject invention. For example, a dose may includeadministering about 0.3 mEq/kg to about 1.0 meq mg/kg daily via an I.V.

Calcium Channel Blockers:

Embodiments may include administering a calcium channel blocker to treata condition in accordance with the subject invention. Embodiments mayinclude orally administering amlodipine besylate (e.g., available underthe brand name NORVASC), e.g., about 5 mgs. to about 20 mgs. daily;diltiazem hydrochloride (e.g., available under the brand names CARDIZEMCD, CARDIZEM SR, DILACOR XR, TIAZAC) at about 30 mgs. to about 360 mgs.four times per day (for example 180 mgs. to about 360 mgs. divided intofour times per day); felodipine plendil at about 2.5 mgs. to about 10mgs. daily; isradipine (e.g., available under the brand names DYNACIRC,DYNACIRC CR) at about 2.5 mgs. daily; nicardipine (e.g., available underthe brand name CARDENE SR) at about 20 mgs. to about 40 mgs. three timesper day; nifedipine (e.g., available under the brand names ADALAT CC,PROCARDIA XL) at about 10 mgs. three times per day; nisoldipine (e.g.,available under the brand name SULAR) at about 10 mgs. to about 20 mgs.daily; and verapamil hydrochloride (e.g., available under the brandnames CALAN SR, COVERA HS, ISOPTIN SR, VERELAN) at about 40 mgs. threetimes per day.

Muscarinics

Embodiments may include administering a muscarinic to treat a conditionin accordance with the subject invention. For example, embodiments mayinclude administering about 5 mgs. of pilocarpine by mouth to a subjectfour times per day, up to about 30 mgs./day.

Sodium Channel Blockers

Embodiments may include administering a sodium channel blocker to treata condition in accordance with the subject invention. For example,embodiments may include administering about 150 mgs. of propafenone bymouth every 8 hours (450 mgs./day) up to about 300 mgs. every 8 hours(90 mgs./day). Embodiments may also include administering about 50 mgs.to about 100 mgs. of flecaimide by mouth about every 12 hours up toabout 400 mgs./day. Embodiments may also include administering about 400mgs. to about 2400 mgs. of tocainide by mouth about every 8 hours.Embodiments may also include administering about 100 mgs. to about 200mgs. of phenytoin by mouth three times per day. Embodiments may alsoinclude administering about 10-30 mgs of about 1% to about 2% lidocaineIM (the maximum individual dosage typically should not exceed about 4.5mg/kg of body weight and generally the maximum total dose should notexceed about 300 mgs.). Embodiments may also include administering about150 mgs. to about 300 mgs. of dispoyramide by mouth about every 6 hoursto about every 12 hours, up to about 1600 mgs. per day. Embodiments mayalso include administering quinidine (e.g., available under the brandname QUINAGLUTE) at about two tablets (648 mgs.; 403 mgs. of quinidinebase) of QUINAGLUTE by mouth about every 8 hours.

Glucocorticoid Receptor Blockers

Embodiments may include administering a glucocorticoid receptor blockerto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering mifepristone my mouth atabout 400 micrograms to about 600 mgs.

Peripheral Adrenergic Inhibitors

Embodiments may include administering a peripheral adrenergic inhibitorto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 5 mgs. to about 75mgs. of guanadrel (e.g., available under the brand name HYLOREL) bymouth e.g., about 5 mgs. two times per day, about 20 to about 75 mgs.per day in divided doses. Embodiments may also include administeringabout 10 mgs. to about 50 mgs. or more per day of guanethidinemonosulfate (e.g., available under the brand name ISMELIN) by mouth.Embodiments may also include administering about 0.05 to about 1.5 mgs.once per day by mouth of reserpine (e.g., available under the brandnames SERPASIL, MECAMYLAMINE, HEXEMETHONIUM). Embodiments may alsoinclude administering about 2.5 mgs. of mecamylamine two times per dayby mouth.

Blood Vessel Dilators

Embodiments may include administering a blood vessel dilator to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 10 mgs. to about 50 mgs. ofhydralazine hydrochloride (e.g., available under the brand nameAPRESOLINE) by mouth four times a day. Embodiments may also includeadministering about 5 mgs. to about 40 mgs. of minoxidil (e.g., e.g.,available under the brand name LONITEN) by mouth once per day.

Central Agonists

Embodiments may include administering a central agonist to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 250 mgs. of alpha methyldopa(e.g., available under the brand name ALDOMET) by mouth three times perday or about 500 mgs. to about 2 grams per day divided into 2 to 4doses. Embodiments may also include administering about 0.1 mgs. toabout 0.6 mgs. of clonidine hydrochloride (e.g., available under thebrand name CATAPRES) by mouth once per day. Embodiments may also includeadministering about 4 mgs. of guanabenz acetate (e.g., available underthe brand name WYTENSIN) by mouth two times per day (up to about 32 mgs.per day). Embodiments may also include administering about 1 mg. toabout 3 mgs. of guanfacine hydrochloride (e.g., available under thebrand name TENEX) by mouth once per day.

Combined Alpha and Beta-Blockers

Embodiments may include administering a combined alpha and beta-blockerto treat a condition in accordance with the subject invention. Forexample, embodiments may include administering about 100 mgs. two timesper day of labetalol hydrochloride (e.g., available under the brandnames NORMODYNE, TRANDATE) by mouth up to about 400 mgs. per day.Embodiments may also include administering about 3.125 mgs. two timesper day of carvedilol (e.g., available under the brand name COREG) bymouth up to about 50 mgs. per day.

Alpha Blockers

Embodiments may include administering an alpha and beta-blocker to treata condition in accordance with the subject invention. For example,embodiments may include administering about 1 mg once per day by mouthof doxazocin mesylate (e.g., available under the brand name CARDURA) upto about 16 mgs. per day. Embodiments may also include administeringabout 0.5 mgs. by mouth of prazosin hydrochloride (e.g., available underthe brand name MINIPRESS) two or three times per day (and may includeabout 6 to about 15 mgs. per day divided into 2 or 3 doses. Embodimentsmay also include administering about 1 mg. of terazosin hydrochloride(e.g., available under the brand name HYTRIN) by mouth once per day, upto about 5 mgs. per day.

Combination Diuretics

Embodiments may include administering a combined diuretic to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 1-2 tablets of amiloridehydrochloride+hydrochlorothiazide (e.g., available under the brand nameMODURETIC) once per day for tablets containing 5 mgs. of anhydrousamiloride HCl and 50 mgs. of hydrochlorothiazide). Embodiments may alsoinclude administering about 25 mgs. to about 50 mgs. once per day bymouth of spironolactone+hydrochlorothiazide (e.g., available under thebrand name ALDACTAZIDE). Embodiments may also include administeringabout 1 to 2 tablets one per day of triamterene+hydrochlorothiazide(e.g., available under the brand names DYAZIDE, MAXZIDE) for tabletscontaining 25 mgs. hydrochlorothiazide and 37.5 mgs. triamterene.

Potassium Sparing Diuretics

Embodiments may include administering a potassium sparing diuretic totreat a condition in accordance with the subject invention. For example,embodiments may include administering about 5 mgs. to about 20 mgs. bymouth once per day of amiloride hydrochloride (e.g., available under thebrand name MIDAMAR). Embodiments may also include administering about 25mgs. to about 200 mgs. once per day by mouth of spironolactone (e.g.,available under the brand name ALDACTONE). Embodiments may also includeadministering about 1 to 2 tablets once per day of triamterene (e.g.,available under the brand name DYRENIUM)) for tablets containing 25 mgs.hydrochlorothiazide and 37.5 mgs. triamterene.

Nitrates

Embodiments may include administering a nitrate to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering isosorbide dinitrate (e.g., available under thebrand name ISODIL) at about 50 to about 40 mgs. orally four times perday or 40 mgs. sustained release orally every 8 to 12 hours. Embodimentsmay also include administering isosorbide mononitrate (e.g., availableunder the brand names ISMO, MONOKET) at about 20 mgs. orally two timesper day and/or may include administering extended release initiallyabout 30 mgs. to about 60 mgs. orally once per day. Maximum of about 240mgs./day. Embodiments may also include administering nitroglycerineointment, e.g., about 0.5 inches q8h and/or about 0.5 to about 2 inchesevery 4 to 6 hours, maximum 4 inches every 4 to 6 hours (0.5 inches isabout 7.5 mgs.). Embodiments may also include administering nitrobid,e.g., orally about 2.5 mgs. to about 9 mgs. 2 to 4 times per day.Embodiments may also include administering a nitroglycerin patch, e.g.,one patch each day applied and removed at bedtime.

Cyclic Nucleotide Monophosphodiesterase (“PDE”) Inhibitors

Embodiments may include administering a cyclic nucleotidemonophosphodiesterase (“PDE”) inhibitor to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering about 5 mgs. to about 20 mgs. once per day ofvardenafil (e.g., available under the brand name LEVITRA) by mouth.Embodiments may also include administering about 10 mgs. to about 20mgs. of tadalafil (e.g., available under the brand name CIALIS) orallyonce per day. Embodiments may also include administering about 25 mgs.to about 100 mgs. of sildenafil (e.g., available under the brand nameVIAGRA) orally once per day.

Alcohols

Embodiments may include administering an alcohol to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering about 200 mgs. orally four times per day or 0.5 toabout 1.0 ml per interspace for subarachnoid injections.

Vasopressin Inhibitors

Embodiments may include administering a vasopressin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering about up to about 6.75 mgadministered via IV of atosiban, e.g., 300 micrograms/min to about 100micrograms/min IV.

Oxytocin Inhibitors

Embodiments may include administering an oxytocin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 0.25 to about IM ofterbutaline, typically not more than about 0.5 mgs. within a four hourperiod. Embodiments may also include administering about 50 microgramsper minute IV of ritodrine, maximum dosage of about 300 micrograms perminute.

Glucagon Like Peptide 1

Embodiments may include administering glucagon like peptide 1 to treat acondition in accordance with the subject invention. For example,embodiments may include administering by I.V. about 200 μg/kg two timesper day. Embodiments may also include administering by SQ infusion about1.25 to about 20 μg/kg.

Relaxin Hormone

Embodiments may include administering a relaxin hormone to treat acondition in accordance with the subject invention. For example,embodiments may include administering 1 to 2 tablets of relaxin by mouththree times per day for tablets of valerian/ayrvedic passion flowerblend (550 mgs.)

Renin Inhibitors

Embodiments may include administering a rennin inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering Aliskiren by mouth at about 2 mgsto about 10 mgs./day.

Estrogen and Analogues (e.g., Estradiols) and Metabolites

Embodiments may include administering estrogen and estrogen analoguesand estrogen metabolites to treat a condition in accordance with thesubject invention. For example, embodiments may include administeringabout 10 mgs. three times per day.

Gonadotropin-Releasing Hormone Inhibitors

Embodiments may include administering a gonadotropin-releasing hormoneinhibitor to treat a condition in accordance with the subject invention.For example, embodiments may include administering leuprolide acetate atabout 65 mgs. SQ (subcutaneous) implant.

Vesicular Monoamine Transport (VMAT) Inhibitors

Embodiments may include administering a VMAT inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering tetrabenazine by mouth at about150 mgs. to about 200 mgs. once per day. Embodiments may also includeadministering reserpine at about 50 micrograms to about 500 microgramsone time per day.

Melatonin

Embodiments may include administering melatonin to treat a condition inaccordance with the subject invention. For example, embodiments mayinclude administering melatonin by mouth at about 0.5 mgs. to about 3.0mgs. once per day.

Testosterone Inhibitors

Embodiments may include administering a testosterone inhibitor to treata condition in accordance with the subject invention. For example,embodiments may include administering spironolactone by mouth at about100 mgs. to about 300 mgs. in divided doses two times per day.Embodiments may include administering cyproterone acetate by mouth atabout 100 mgs. to about 150 mgs. once per day.

Dipeptidyl Peptidase (DP) IV Inhibitors (DP4 Inhibitors)

Embodiments may include administering a DP4 inhibitor to treat acondition in accordance with the subject invention. For example,embodiments may include administering LAF237 by mouth at about 25 mgs.to about 200 mgs. per day.

Anti-Coagulants

Embodiments may include administering an anti-coagulant to treat acondition in accordance with the subject invention. For example,embodiments may include administering about 0.25 mg/kg intravenous bolusof abciximab and/or a continuous intravenous infusion of about 0.125 mg/kg/min (to a maximum of about 10 m g/min) for a period of time, e.g.,12 hours. Embodiments may include administering dipridamole (e.g.,AGGRENOX or the like) orally, e.g., one capsule twice daily. Embodimentsmay include administering anagrlide (e.g., AGRILYN or the like) orally,e.g., initially 0.5 mg orally four times daily or 1 mg orally twicedaily or lowest effective dose- to a maximum 10 mg/day. Embodiments mayinclude administering clopiogrel (e.g., PLAVIX or the like) at 75 mgorally once daily. Embodiments may include administering dipridamole(e.g., PERSANTINE or the like) at 75 to 100 mg orally four times daily.Embodiments may include administering eptifibatide (e.g., INTEGRILIN orthe like) via IV at 0.5 mcg/kg/min to 180 mcg/kg or 135 mcg/kg and/or(e.g., followed by) 0.5 mcg/kg/min×20-24 hours. For example IV bolus of180 mcg/kg over 1-2 minutes followed by 2 mcg/kg/min (maximum 15 mg/hr)up to 72 hours. Embodiments may include administering ticlopidine (e.g.,TICLID or the like) at 250 mg orally twice daily. Embodiments mayinclude administering tirofibam (e.g., AGGRASTAT or the like) at 0.4mcg/kg/min to 0.1 mcg/kg/min. Embodiments may include administeringardeparin (e.g., NORMIFLO or the like) at 50 units SC every 12 hours.Embodiments may include administering dalteparin (e.g., FRAGMIN or thelike) at 2500 units to 5000 units SC one daily or 120 units/kg to about10,000 SC every 12 hours. Embodiments may include administeringenoxaparin (e.g., LOVENOX or the like) at 30-40 mg SC once daily.Embodiments may include administering lepirudin (e.g., REFLUDAN or thelike) at 0.4 mg/kg (max weight of 110 kg) over a 15-20 seconds followedby does of 0.15 mg/kg/hr (max weight of 110 kg)×2-10 days as needed.Embodiments may include administering alteplase (e.g., ACTIVASE), t-PAor the like) at 15 mg to 35 mg via IV, e.g., 15 mg via IV bolus followedby 30-35 mg via N over about 60 minutes. Embodiments may includeadministering reteplase (e.g., RETEVASE or the like) at 10.8 units IVover 2 minutes repeated in 30 minutes. Embodiments may includeadministering streptokinase at 1.5 million units N over 60 minutes.Embodiments may include administering aminocaproic acid (e.g., AMICAR orthe like) at 4 to 5 grams orally or IV over 1 hour, then 1 gram asneeded. Embodiments may include administering cilostazol (e.g., PLETALor the like) at 50 to 100 mg orally twice daily. Embodiments may includeadministering pentoxifylline (e.g., TRENTAL or the like) at 400 mgorally three times daily with meals.

Beta Agonists:

As described above, embodiments may include administering an effectiveamount of a beta agonist to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administering dosagesof about 0.5 to about 1.0 micrograms/kilogram/minute of dobutamineintravenously, e.g., dosages of about 500 micrograms/ml to about 2000micrograms/ml may be administered. Embodiments may include administeringdosages of terbutaline at about 0.25 mg to about 0.5 mg intramuscularly(“IM”), e.g., not more than about 0.5 mg within a four hour period.Embodiments may include administering dosages of ritodrine at about 50to about 350 micrograms per minute intravenously. Embodiments mayinclude administering dosages of albuterol via nebulizer at about 0.5 mlof 0.5% inhalation solution with about 2.5 ml sterile saline solutiongiven over about 5 to about 15 minutes three to four times per day.Embodiments may include administering dosages of metaproterenol vianebulizer every four hours wherein a vial containing 0.4% metaproterenolsulfate is equivalent to 0.2 ml of metaproterenol sulfate inhalationsolution 5% diluted to 2.5 ml with normal saline.

Alpha Agonists:

As described above, embodiments may include administering an effectiveamount of an alpha agonist to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administering dosagesof phenylephrine, e.g., subcutaneously or intramuscularly: from 1 mg toabout 10 mg., wherein the initial dose generally should not exceed 5mg.; intravenously: from about 0.1 mg to about 0.5 mg., whereingenerally the initial dose should not exceed 0.5 mg. Injections aretypically not repeated more often than about every 10 to 15 minutes.Embodiments may include administering dosages of metaraminolsubcutaneously at about 2 to about 10 mg for an interval of about 10minutes.

Prednisone and Steroids:

As described above, embodiments may include administering an effectiveamount of prednisone or a steroid to a subject during at least one phaseof the subject's menstrual cycle. Embodiments may include administeringdosages of prednisone or a steroid by mouth at about 5 to about 60mg/day, once per day. For example, prednisone may be in the form of asolution, syrup or tablet and doses may be given once daily or everyother day and about 2.5-15 mg may be taken by a subject 2-4 times daily.

Indirect Agents that Include Norepinephrine:

As described above, embodiments may include administering an effectiveamount of an indirect agents that include norepinephrine to a subjectduring at least one phase of the subject's menstrual cycle. Embodimentsmay include administering dosages of ephedrine IM or IV at about 25 toabout 50 mg once per day. Embodiments may include administering dosagesof phenylpropanolamine by mouth at about 25 mg every four hours, up toabout 150 mg/day. Embodiments may include administering dosages ofamphetamine by mouth at about 2.5 mg to about 60 mg once per day.

Epinephrine:

As described above, embodiments may include administering an effectiveamount of epinephrine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include intravenouslyadministering epinephrine at about 0.1 to about 0.25 mg (about 1 toabout 2.5 ml of 1:10,000 solution) once every 20 to 30 minutes.

Norepinephrine:

As described above, embodiments may include administering an effectiveamount of norepinephrine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include intravenouslyadministering norepinephrine at about 0.5 to about 1.0 mg (about 5 toabout 10 ml of 1:10,000 solution) once every 5 minutes.

Potassium Channel Blockers and Magnesium Channel Blockers:

As described above, embodiments may include administering an effectiveamount of a potassium channel blocker or a magnesium channel blocker toa subject during at least one phase of the subject's menstrual cycle.Embodiments may include administering lithium by mouth at about 10 toabout 60 mg/kg once per day. Embodiments may include administeringvalproate by mouth at about 10 to about 60 mg/kg once per day.

Acetylcholine

As described above, embodiments may include administering an effectiveamount of acetylcholine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administeringacetylcholine in the form of eye drops at about 0.75 to about 10milligrams/ml acetylcholine.

Cocaine:

As described above, embodiments may include administering an effectiveamount of cocaine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administering cocainetopically on mucus membranes, e.g., about 10% cocaine hydrochloride.

Amphetamines:

As described above, embodiments may include administering an effectiveamount of an amphetamine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administering anamphetamine by mouth at about 5 to about 10 mg per day, e.g., 10 mg/dayin divided doses.

Ephedrine:

As described above, embodiments may include administering an effectiveamount of ephedrine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administeringephedrine sulfate injection at about 10 to about 50 mg injectedsubcutaneously or intramuscularly (equivalent to 0.2 to 1.0 ml of 5%solution).

Terbutaline:

As described above, embodiments may include administering an effectiveamount of terbutaline to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administeringterbutaline intramuscularly at about 0.25 mg, e.g., one time, andtypically not more than about 0.5 mg within a 4 hour period.

Dopamine:

As described above, embodiments may include administering an effectiveamount of dopamine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administeringdopamine intravenously at about 2 to about 50 microgram/kg/minute,wherein each milliliter of a 40 mg/ml preparation contains 40 mg ofdopamine hydrochloride (equivalent to 32.31 mg of dopamine base).Embodiments may also include administering levodopa (L-dopa) incombination with carbidopa taken by mouth, e.g., about 25 mg carbidopa(up to about 2500 mg per day) and about 100 mg levodopa one half tablet,daily. Embodiments may also include administering bromocriptine (e.g.,available under the brand name PARLODEL) by mouth at about 1.25 to about100 mg per day.

Dobutamine:

As described above, embodiments may include administering an effectiveamount of dobutamine to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include intravenouslyadministering dobutamine at about 0.5 to about 1.0 microgram/kg/min (upto about 500 microgram/ml).

Antidiuretic Hormone (“ADH”) (Also Known as Vasopressin):

As described above, embodiments may include administering an effectiveamount of ADH to a subject during at least one phase of the subject'smenstrual cycle. Embodiments may include subcutaneously orintramuscularly administering about 5 to about 10 units of AHD two orthree times per day.

Oxytocin:

As described above, embodiments may include administering an effectiveamount of oxytocin to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include intravenouslyadministering oxytocin (e.g., available under the brand name PITOCIN) atabout 1 to about 2 mU/mm (solution of 1 ml (10 units) combined with1,000 ml of a non hydrating diluent).

THC Cannabinoids:

As described above, embodiments may include administering an effectiveamount of THC cannabinoid to a subject during at least one phase of thesubject's menstrual cycle. Embodiments may include administering THCcannabinoid by rectal suppository at about 2.5 mg two times per day; orabout 10 to about 20 mg one, two or three times per day by mouth; or 1mg intravenously, e.g., one time; or about 200 mg once per day by mouth.

In certain embodiments, a given pharmacological agent may beadministered at or near the time of a particular phase of a subject'smenstrual cycle, i.e., in close temporal proximity to, including during,one or more predetermined phases of a subject's menstrual cycle. Forexample, embodiments of the subject methods may include administrationof a pharmacological agent to achieve a particular parasympatheticactivity/sympathetic activity ratio during at least a portion of themenses phase and/or follicular phase and/or the ovulation phase and/orthe luteal phase. Of interest is the administration of a pharmacologicalagent at least near the time of, or during at least a portion of, theluteal phase and/or menses phase to modulate the autonomic nervoussystem to increase the parasympathetic activity/sympathetic activityratio to treat the condition of interest. For example, embodiments mayinclude determining the occurrence (predetermining the occurrence) ofone or more phases of a subject's menstrual cycle, e.g., the lutealphase, and administering at least one pharmacological agent to increasethe parasympathetic activity/sympathetic activity ratio during the oneor more predetermined phases, e.g., during the luteal phase, afterovulation, or at a time prior to the start of the luteal phase and/orthroughout all of or a portion of the luteal phase. Embodiments mayinclude determining the occurrence of the menses phase and administeringat least one pharmacological agent to increase the parasympatheticactivity/sympathetic activity ratio during the menses phase, or at atime prior to the start of the menses phase and/or throughout all of ora portion of the menses phase. Similar treatment protocols may beemployed for the follicular and ovulation phases.

The luteal phase is the part of the cycle that starts at ovulation andends the day before a female's next period and usually lasts betweenabout 12 to about 16 days. As such, embodiments of the subject inventionmay include administering an effective amount of a pharmacological agentat least one time during ovulation and/or at least one time during theluteal phase to increase the parasympathetic activity/sympatheticactivity ratio in a manner effective to treat a condition, whereembodiments may include administration during about all of the days of asubject's luteal phase or the late luteal phase. By “late luteal phase”is meant the later half of the luteal phase. For example, if a subject'sluteal phase is determined to last about 14 days, the late luteal phasemay be considered to be from about day 7 to about day 14 of the lutealphase.

As embodiments of the subject methods include administering an effectiveamount of at least one pharmacological agent to a subject during atleast one predetermined menstrual phase, embodiments of the subjectmethods include determining the occurrence of the phases or at least onephase of a subject's menstrual cycle by any suitable method, e.g., usinghormone-specific blood tests, urine tests, etc., as is known to those ofskill in the art. For example, the onset of the luteal phase may bedetermined using a urine leutinizing hormone (“LH”) detection test orkit, as are known in the art, e.g., as available under the brand namesOVUQUICK ONE-STEP, CLEARPLAN EASY and SURESTEP. Other known methods maybe employed as well and include empirical and non-empirical methods suchas estimating the start, duration and/or end of a particular menstrualcycle phase, e.g., by a calendar method (counting days) or the like.Regardless of the particular method employed, in certain embodiments theonset of ovulation and/or the luteal phase and/or any other menstrualcycle phase may be determined and one or more of the pharmacologicalagents described above may be administered at or near the predeterminedstart of the subject's luteal phase and/or during at least part of asubject's determined luteal phase.

Electrical Modulation of at Least a Portion of the Autonomic NervousSystem

As described above, embodiments of the subject invention may alsoinclude electrically modulating at least a portion of the autonomicnervous system to increase the parasympathetic activity/sympatheticactivity ratio. By “electrically modulating at least a portion of asubject's autonomic nervous system” is meant altering or changing atleast a portion of an autonomic nervous system by applying electricalenergy to provide a change, alteration or shift in at least onecomponent or aspect of the autonomic nervous system, as will bedescribed in greater detail below. The electrical modulation of theautonomic nervous system may affect central motor output and/or nerveconduction and/or transmitter release and/or synaptic transmissionand/or receptor activation, but in any event is a change that providesan increase in the parasympathetic activity/sympathetic activity ratio.

For example, embodiments may include electrically modulating at least aportion of a subject's autonomic nervous system to alter, shift orchange the activity in at least one of the sympathetic system andparasympathetic system from a first state to a second state, where thesecond state is characterized at least by an increase or decrease in theparasympathetic activity/sympathetic activity ratio relative to thefirst state. Electrical energy may be employed to increase and/ordecrease activity in at least a portion of the autonomic nervous system.For example, embodiments may include electrically modulating at least aportion of the autonomic nervous system to achieve one or more of thefollowing (but in any event to achieve a net result of an increase ordecrease in parasympathetic activity/sympathetic activity ratio,relative to the parasympathetic activity/sympathetic activity ratioprior to pharmacological modulation): (1) increasing activity in atleast one parasympathetic nerve fiber to achieve an increase in activityin at least a portion of the parasympathetic system, (2) increasingactivity in at least one sympathetic nerve fiber to achieve an increasein activity in at least a portion of the sympathetic system, (3)inhibiting activity in at least one parasympathetic nerve fiber toachieve a decrease in activity in at least a portion of theparasympathetic system, and (4) inhibiting activity in at least onesympathetic nerve fiber to achieve a decrease in activity in at least aportion of the sympathetic system. Certain embodiments of the subjectinvention may include electrically modulating the autonomic nervoussystem to both increase activity in at least a portion of the autonomicnervous system, e.g., increase activity in at least one parasympatheticnerve fiber, and inhibit activity in at least a portion of the autonomicnervous system, e.g., inhibit activity in at least one sympathetic nervefiber, to treat a condition. Accordingly, embodiments of the subjectmethods include providing electrical energy to at least a portion of asubject's autonomic nervous system, where such electrical energy may beexcitatory (to increase activity) or inhibitory (to decrease activity)and in certain embodiments may be both excitatory and inhibitoryenergies.

As noted above, electrical modulation in accordance with the subjectinvention may be performed prior to and/or at the same time and/orsubsequent to any other medical or clinical treatment regime such as anyof those described above, for example, pharmacological modulation of atleast a portion of the subject's autonomic nervous system. In otherwords, the subject methods may include other, concomitant therapies ortreatments to treat the same or different condition that do not employelectrical energy.

According to embodiments of the subject invention, electrical modulationis accomplished by at least administering electrical energy to a subjectin a manner sufficient to treat the subject for a condition caused,precipitated or otherwise exacerbated, influenced or affected by theratio of the parasympathetic activity/sympathetic activity ratio. Inother words, activity in at least a portion of the autonomic nervoussystem is at a level that is at least contributing to or otherwiseaffecting or exacerbating a condition such a disease condition in needof treatment, and as such modulation of the autonomic nervous system maybe employed to treat the condition.

Methods and devices suitable for use in electrically modulating aportion of subject's autonomic nervous system, and which may be employedin the practice of the subject invention, are described in detail incopending U.S. application Ser. No. 10/661,368, entitled “Treatment ofConditions Through Electrical Modulation of the Autonomic NervousSystem”, the disclosure of which is herein incorporated by reference.

In general, modulating at least a portion of the autonomic nervoussystem using electrical energy may be accomplished with the use of anelectric energy applying devices (also referred to as electrical energysupplying or delivering devices), such as, e.g., described in theabove-noted copending patent application. Once an electric energyapplying device is positioned in a suitable position on or about one ormore targeted areas of the autonomic nervous system such as one or moreparasympathetic nerve fibers and/or one or more sympathetic nervefibers, electrical energy is applied to the area(s) (e.g., the targetednerve fiber(s)) for a period of time sufficient to provide the desiredmodulation of the autonomic nervous system. This period of time willvary depending on the area (e.g., the nerve fiber) being treated, thecondition being treated, the particulars of the device used, etc.

As described in greater detail below, certain embodiments includesimultaneously monitoring (i.e., in “real time”) the parasympatheticactivity and/or sympathetic activity such that electrical energy isapplied until the desired increase in parasympatheticactivity/sympathetic activity ratio is observed. Still further, in manyembodiments once the desired ratio is achieved, electrical energy may berepeatedly applied thereto one or more times to maintain the desiredstate such that the subject methods may be repeated one or more times,i.e., the subject methods include chronic administration of electricalenergy to at least one area of the autonomic nervous system. Forexample, in certain embodiments electrical energy (e.g., intermittentmild electrical pulses) may be delivered to a given area of theautonomic nervous system twenty-four hours a day for a period of days,weeks, months, years or even the entire lifetime of the subject incertain embodiments during one or more predetermined menstrual cyclephases. For example, electrical energy may be delivered to a given areaduring one or more predetermined phases of a subject's menstrual cyclesuch as during a predetermined luteal phase or the like every month formonths, years or even the entire lifetime of the subject.

During the period of time that a given area of the autonomic nervoussystem is electrically modulated, the electrical energy may be appliedsubstantially continuously, including continuously, or intermittently(i.e., pulsed or periodic), where in many embodiments the electricalenergy is in the form of electrical pulses. In other words, in certainembodiments a given area of the autonomic nervous system (e.g., a givennerve fiber) may be continuously contacted with electrical energy duringthe above-described period of time and in certain other embodiments agiven area of the autonomic nervous system (e.g., a given nerve fiber)may be pulsed or intermittently contacted with electrical energy duringthe period of time described above.

In accordance with embodiments of the subject methods to electricallymodulate at least one area of the autonomic nervous system, onceoperatively positioned the electrical energy applying device isactivated to provide an electrical signal to the targeted area such asto one or more nerve fiber(s) in a manner to increase or decrease theparasympathetic activity/sympathetic activity ratio at least in theparticular area being contacted with electrically energy and in certaininstances in adjacent areas or in the entire autonomic system, e.g.,systemically in certain instances. For example, many nerve fibers are inclose proximity and thus application of electrical energy to one nervefiber may also increase or decrease activity in one or more other nervefibers, e.g., nerve fibers in close proximity thereto.

In practicing the subject methods, activation of the electrical energysupplying device directly applies the electrical output of the device,i.e., electrical energy, to the targeted area. For example, electrodesmay be positioned to direct electrical impulses to specific nervefibers, etc. The exact parameters of the protocol may vary depending onthe particular subject, condition being treated, etc. An electroniccurrent wave may be provided when the electrical energy is applied. Incertain embodiments, the current wave includes current waves of highfrequency, e.g., high frequency pulses, where the current wave may alsoinclude low frequency amplitude modulation. In certain embodiments, aplurality of high frequency bursts of current pulses may be applied inaddition to the application of underlying low frequency continuousstimulus. Monopolar or multipolar technologies may be employed.

For example, to increase activity in a portion of the autonomic nervoussystem, voltage or intensity may range from about 1 millivolt to about 1volt or more, e.g., 0.1 volt to about 50 volts, e.g., from about 0.2volt to about 20 volts and the frequency may range from about 1 Hz toabout 2500 Hz, e.g., about 1 Hz to about 1000 Hz, e.g., from about 2 Hzto about 100 Hz in certain embodiments. In certain embodiments a pured-c voltages may be employed. The pulse width may range from about 1microsecond to about 2000 microseconds or more, e.g., from about 10microseconds to about 2000 microseconds, e.g., from about 15microseconds to about 1000 microseconds, e.g., from about 25microseconds to about 1000 microseconds. The electrical output may beapplied for at least about 1 millisecond or more, e.g., about 1 second,e.g., about several seconds, where in certain embodiments thestimulation may be applied for as long as about 1 minute or more, e.g.,about several minutes or more, e.g., about 30 minutes or more may beused in certain embodiments.

To inhibit activity or conduction in a portion of the sympatheticnervous system, voltage or intensity may range from about 1 millivolt toabout 1 volt or more, e.g., 0.1 volt to about 50 volts, e.g., from about0.2 volt to about 20 volts and the frequency may range from about 1 Hzto about 2500 Hz, e.g., about 50 Hz to about 2500 Hz. In certainembodiments a pure d-c voltages may be employed. The pulse width mayrange from about 1 microseconds to about 2000 microseconds or more,e.g., from about 10 microseconds to about 2000 microseconds, e.g., fromabout 15 microseconds to about 1000 microseconds, e.g., from about 25microseconds to about 1000 microseconds. The electrical energy may beapplied for at least about 1 millisecond or more, e.g., about 1 second,e.g., about several seconds, where in certain embodiments the electricalenergy may be applied for as long as about 1 minute or more, e.g., aboutseveral minutes or more, e.g., about 30 minutes or more may be used incertain embodiments.

The time period for modulating at least a portion of a subject'sautonomic nervous system using electrical energy is analogous to thatdescribed above for pharmacologically modulating at least a portion of asubject's autonomic nervous system.

A variety of different devices for applying electrical energy toincrease or inhibit activity in at least a portion of the autonomicnervous system in accordance with the subject invention may be employedas described in the above referenced, copending U.S. application Ser.No. 10/661,368, the disclosure of which is herein incorporated byreference. Electrical energy delivering devices that may be used topractice the subject invention may be positioned directly on a targetedarea, e.g., positioned below the skin of a subject directly on oradjacent a portion of the autonomic nervous system (e.g., one or morenerve fibers) such as an implantable device, or may be an externaldevice (i.e., some or all of the device may be external to the subject).In accordance with embodiments of the subject invention, one or moreelectrodes or electrical contacts may be positioned directly on oradjacent a targeted area of the autonomic nervous system, i.e., directlyon or adjacent a portion of the parasympathetic and/or sympatheticsystem, where the one or more electrodes may be surgically implanteddirectly on or adjacent a targeted nerve fiber of a subject. In furtherdescribing the subject invention, a single electrode is describedhowever it is to be understood that multiple electrodes may be employedand features and characteristics of the single electrode describedherein are applicable to any other electrodes that may be employed inthe practice of the subject invention.

Electrical energy delivering devices that may be employed in thepractice of the subject methods typically include a stimulator (orinhibitor) such as an electrode, a controller or programmer and one ormore connectors for connecting the stimulating device to the controller.In certain embodiments more than one electrode may be employed. Infurther describing representative electrodes, such are described in thesingular, but it will be apparent that more than one electrode may beused, where such may be the same or may be different in one or moreaspects. Accordingly, the description of a representative electrodesuitable for use in the subject methods is applicable to otherelectrodes that may be employed.

The electrode employed in the subject invention is typicallycontrollable to provide output signals that may be varied in voltage,frequency, pulse width, current and intensity. The electrode istypically one that provides both positive and negative current flow fromthe electrode and/or is capable of stopping current flow from theelectrode and/or changing the direction of current flow from theelectrode. For example, embodiments include an electrode that iscontrollable in these respects, i.e., controllable in regards toproducing positive and negative current flow from the electrode, stopcurrent flow from the electrode, change direction of current flow fromthe electrode, and the like. In certain embodiments, the electrode hasthe capacity for variable output, linear output and short pulse width.

The energy source for the electrical output is provided by a battery orgenerator such as a pulse generator that is operatively connected to theelectrode. The energy source may be positioned in any suitable locationsuch as adjacent to the electrode (e.g., implanted adjacent theelectrode), or a remote site in or on the subject's body or away fromthe subject's body in a remote location and the electrode may then beconnected to the remotely positioned energy source using wires, e.g.,may be implanted at a site remote from the electrode or positionedoutside the subject's body in certain instances. Implantable generatorsanalogous to a cardiac pacemaker may be used in certain embodiments.

The electrode may be mono-polar, bipolar or multi-polar. In order tominimize the risk of an immune response triggered by the subject againstthe device and minimize damage such as corrosion and the like to thedevice from other biological fluids, etc., the electrode and any wiresand optional housing materials are made of inert materials such as forexample silicon, metal, plastic and the like. For example, a multi-polarelectrode having about four exposed contacts (e.g., cylindrical contactsmay be employed.

A variety of methods may be used to endoscopically or surgically implantthe electrode on or adjacent at least a portion of the autonomic nervoussystem such as on or adjacent one or more nerve fibers of theparasympathetic nervous system and/or sympathetic system, where suchmethods are known to those of skill in the art. Because some nervefibers may be in very close proximity to one another within a very smallarea, an analogous technique may generally be employed to provideoperable placement of the electrode on or adjacent to any targeted areaof the autonomic nervous system.

A controller or programmer is also typically included in an electricalenergy supplying device. The programmer is typically one or moremicroprocessors under the control of a suitable software program. Othercomponents of the programmer will be apparent to those of skill in theart, e.g., analog to digital converter, etc.

The electric energy supplying device employed in the practice of thesubject methods may be pre-programmed for desired parameters. In manyembodiments the parameters are controllable such that the electrodesignal may be remotely modulated to desired settings without removal ofthe electrode from its targeted position. Remote control may beperformed, e.g., using conventional telemetry with an implanted electricsignal generator and battery, an implanted radiofrequency receivercoupled to an external transmitter, and the like. In certainembodiments, some or all parameters of the electrode may be controllableby the subject, e.g., without supervision by a physician. For example, amagnetic signal may be employed. In such embodiments, one or moremagnets may be employed such that upon bringing a magnet in proximity toor away from the power source such as a pulse generator, the magnet maybe employed to interfere with the electronic circuitry thus modulatingthe power—either increasing or decreasing the power supplied dependingon whether the magnet is brought in proximity or moved away from thepower source.

The present invention may be operated as an open-loop controlled system.In an open-loop system, the physician or patient may at any timemanually or by the use of pumps or motorized elements adjust treatmentparameters such as pulse amplitude, pulse width, pulse frequency, orduty cycle. Optionally, the present invention may incorporate aclosed-loop control system which may automatically adjust the electricalparameters in response to a sensed symptom or an important relatedsymptom indicative of the extent of the condition being treated. Under aclosed-loop feedback system to provide automatic adjustment ofparameters of the electrodes, a sensor that senses a condition of thebody is utilized. In certain embodiments, such a condition may be aparticular phase of the menstrual cycle (e.g., may sense hormonalchanges or the like). More detailed descriptions of sensors that may beemployed in the practice of the subject invention, and other examples ofsensors and feedback control techniques that may be employed aredisclosed in U.S. Pat. No. 5,716,377, which is incorporated herein byreference.

Operative placement of a suitable electric energy supplying device maybe accomplished using any suitable technique. In general, such placementincludes localization of an area of the autonomic nervous system,positioning the electrode on or adjacent the area and attaching theelectrode to a power source. However, with regard to attaching theelectrode to a power source, it should be understood that electrodes maybe employed which make the implantation and/or attachment of a separatepower source unnecessary. For example, an electrode may be employedwhich includes its own power source, e.g., which is capable of obtainingsufficient power for operation from surrounding tissues in the patient'sbody or which may be powered by bringing a power source external to thepatient's body into contact with the patient's skin, or may include anintegral power source, and the like. In such instances, the surgicalprocedure may be completed upon implantation of the electrode on oradjacent to the area of interest.

An electrode introducer needle may be employed to implant the electrodeon or proximate to the area of interest. The size of the introducerneedle may vary depending on the diameter of the electrode, etc., wherein certain embodiments the electrode introducer needle may be a12-gauge, 14-gauge, 16-gauge, 18-gauge, 20-gauge needle or 22-gaugeneedle, e.g., an electrode introducer needle available from Radionics inthe Sluyter-Mehta kit as SMK 100 mm 2 mm active tip cannula. However, itshould be understood that other electrode introducer needles may be usedas appropriate to the needs and skill level of the practitionerperforming the surgical procedure.

At least one imaging apparatus such as a CT scan, MRI apparatus,ultrasound apparatus, fluoroscope, or the like, may be employed tomonitor the surgical procedure during the localization of a given area,e.g., to assist in determining a suitable entry point for the insertionof the electrode.

Once the entry point is determined, the skin overlying the entry pointis shaved and prepared with antiseptic solution. A 25-gauge needle maybe used to inject a subcutaneous local anesthetic (such as, for example,2 cc of 2% lidocaine) into the skin and subcutaneous tissues overlyingthe entry point. In addition to the local anesthetic, the patient may begiven intravenous sedation and prophylactic antibiotics prior tocommencement of the implantation procedure if desired.

The electrode introducer needle is inserted at the entry point andadvanced. The fluoroscope may be adjusted as the needle is advanced.Once the needle is suitably positioned, the stylet is withdrawn from theelectrode introducer needle. A “test” electrode, if employed, used totest the placement of the electrode introducer needle may then bepositioned within the central channel of the needle. If a “test”electrode is not employed, the electrode that is to be employed tomodulate the autonomic nervous system may then be positioned within thecentral channel of the needle. The electrode may then be advanced to thedistal tip of the needle to place the electrode on or proximate to thearea of interest.

In certain embodiments, the “test” electrode, if employed, may be aradiofrequency stimulating electrode suitable to electrically stimulatethe tissue at the end of the tip of the electrode and verify itsposition physiologically within the patient, which may be a differentelectrode than that ultimately implanted within the patient. A suitableradiofrequency stimulating electrode may be 10 cm with a 2-mmnon-insulated active tip. Once the “test” electrode is inserted throughthe electrode introducer needle with its electrical contacts exposed, itmay then be connected to an electrical stimulus/lesion generator forelectrical stimulation.

The frequency of stimulation may be set at any suitable frequency, e.g.,at about 50 Hz, and the voltage may be gradually increased until thesubject reports acknowledgement of application of electrical current,e.g. reports stimulation, of or about the area of interest of theautonomic nervous system. Repositioning of the electrode may beperformed as necessary.

If a “test” electrode is employed to test the placement of the electrodeintroducer needle and as such is different from the electrode to beemployed to modulate the autonomic nervous system (i.e., the electrodeto be implanted if it is desired to implant the electrode that will beemployed to modulate the autonomic nervous system), the “test” electrodemay then be removed from the electrode introducer needle while theneedle is held firmly in place to prevent displacement. The electrode tobe implanted may then be inserted through the central channel of theneedle while the needle is held in place at the hub. Once the electrodeto be implanted is in position, fluoroscopic imaging and electricalstimulation may be employed to verify the correct positioning of theneedle and the electrode. Alternatively, if the electrode used to testthe placement of the electrode introducer needle is the electrode to beimplanted, the electrode may be left in the final test position.

Once the implanted electrode is in place, the end of the electrode thatis outside the skin is carefully held in place against the skin. Theelectrode introducer-needle may then be slowly removed, leaving theimplanted electrode in place. At this point, if desired, a few smallsubcutaneous sutures may be placed around the electrode to hold it inthe desired position.

Once the needle has been completely removed and the implanted electrodeis in the final position, then the proximal part of the electrode thatis coming out of the skin may be secured to the skin of the subject,e.g., by adhesive tape. Additionally, a small incision may be made onthe skin at the area the electrode exits the body. Then severalsubcutaneous sutures may be placed around the electrode to hold it inplace. The distal end of the electrode may then be connected to anextension wire or catheter, which is tunneled to the subclavicular area,or another region which will house the device used as an energy sourcefor the implanted electrode. The device or devices used to control orstimulate the electrode may be surgically implanted in the desiredregion by procedures known in the art, such as have been applied insurgical neuromodulation therapies used to treat Parkinson's disease.

Electrical modulation may be performed at any suitable time, where suchincludes times analogous to those described above for pharmacologicalmodulation. For example, electrical modulation may be performed at ornear the time of a particular phase of a subject's menstrual cycle,i.e., in close temporal proximity to, including during, one or morepredetermined phases of a subject's menstrual cycle. For example,embodiments of the subject methods may include electrically modulatingat least a portion of a subject's autonomic nervous system to achieve aparticular parasympathetic activity/sympathetic activity ratio (e.g., anormal ratio) during at least a portion of the menses phase and/orfollicular phase and/or the ovulation phase and/or the luteal phase. Ofinterest is electrical modulation at least near the time of, or duringat least a portion of, the luteal phase and/or menses phases to modulatethe autonomic nervous system to increase or decrease the parasympatheticactivity/sympathetic activity ratio. For example, embodiments mayinclude electrical modulation of at least a portion of the autonomicnervous system to increase the parasympathetic activity/sympatheticactivity ratio during the luteal phase, after ovulation. For example,embodiments may include determining the occurrence of one or more phasesof a subject's menstrual cycle, e.g., the luteal phase, and applyingelectrical energy to at least a portion of the autonomic nervous systemto increase the parasympathetic activity/sympathetic activity ratioduring the one or more predetermined phases, e.g., during the lutealphase, or at a time prior to the start of the luteal phase and/orthroughout all of or a portion of the luteal phase. Embodiments mayinclude determining the occurrence of the menses phase and applyingelectrical energy to increase the parasympathetic activity/sympatheticactivity ratio during the menses phase, or at a time prior to the startof the menses phase and/or throughout all of or a portion of the mensesphase. Similar treatment protocols may be employed for the follicularand ovulation phases.

Embodiments of the subject invention may include electrically modulatingat least a portion of a subject's autonomic nervous system at least onetime during at least one predetermined menstrual cycle phase to increaseor decrease the parasympathetic activity/sympathetic activity ratio,where embodiments may include electrically modulating at least a portionof a subject's autonomic nervous system during about all of the days ofa subject's luteal phase and/or menses phase. In such instances, thesubject methods typically include determining the occurrence of one ormore phases of a subject's menstrual cycle by any suitable method asdescribed above, e.g., using hormone-specific blood tests, urine tests,etc., as is known to those of skill in the art. For example, the onsetof the luteal phase may be determined using a urine leutinizing hormone(“LH”) detection test or kit, as are known in the art, e.g., asavailable under the brand names OVUQUICK ONE-STEP, CLEARPLAN EASY andSURESTEP. Other known methods may be employed as well and includeempirical and non-empirical methods such as estimating the start,duration and/or end of a particular menstrual cycle phase, e.g., by acalendar method (counting days) or the like. Regardless of theparticular method employed, the occurrence of one or more menstrualcycle phases may be determined and electrical modulation at least aportion of the subject's autonomic nervous system as described above maybe performed at or near the determined start of the subject's determinedmenstrual cycle phase.

Regardless of how the autonomic nervous system is modulated(pharmacologically, electrically, etc.), certain embodiments of thesubject methods may also include detecting, monitoring, observing, etc.,information related to one or more aspects of the autonomic nervoussystem such as a physical and/or chemical aspect, e.g., activity,balance, etc., in at least a portion of the autonomic nervous system,e.g., in at least a portion of the sympathetic nervous system and/orparasympathetic system, and evaluating this information to determine thestate of the autonomic nervous system, e.g., the parasympatheticactivity and/or sympathetic activity. Once the state of the autonomicnervous system is determined, it may be evaluated in regards to whetherthe autonomic nervous system is in need of modulation, i.e., whether theparasympathetic activity/sympathetic activity ratio needs to beincreased to treat a condition such that this analysis may be employedas a “trigger” to modulating or further modulating at least a portion ofthe autonomic nervous system wherein modulation may not be otherwiseperformed unless the analysis determined such is necessary.

Accordingly, collecting and evaluating this type of data and relating itto whether autonomic nervous system modulation is required may beemployed as a “trigger” to pharmacologically modulating at least aportion of the autonomic nervous system (e.g., performed prior to,during or following a particular autonomic nervous system modulationprotocol whether performed using pharmacological methods, electricalenergy methods or other methods) such that such data may indicatewhether, when, etc., modulation is required—if at all. For example, incertain embodiments modulation of at least a portion of a subject'sautonomic nervous system may not be performed unless one or more aspectsof the autonomic nervous system are detected and indicate suchmodulation is necessary. Any suitable physical and/or chemical aspect orindicator of the autonomic nervous system may be employed, e.g., amountsof T helper cells (Th1 and/or Th2), conduction, catecholamine levels,heart rate variability (“HRV”), respiratory sinus arrhythmia, actionpotentials, QT interval, as well as chronotropic, inotropic, andvasodilator responses. For example, in certain embodiments HRV measuressuch as low frequency peak (“LF”), high frequency peak (“HF”), and theLF/HF ratio may be used as indicators of different aspects of theautonomic nervous system. Typically, in normal females, normalized units(“NU”) of LF and LF/HF ratio are higher, and NU of HF are lower, duringthe luteal phase. In certain embodiments, particular hormonal levels,e.g., associated with a particular phase of the menstrual cycle, may bedetected. In certain embodiments, detection may include detecting theactivity or function of a particular organ or system under the controlof the autonomic nervous system. Other exemplary measurements mayinclude, but are not limited to, plasma volume, effective renal plasmavolume, effective renal blood flow, norepinephrine, and concentrationsof rennin-angiotensin-aldosterone system hormones, which have been notedto be higher during the luteal phase than in the follicular phase. Anysuitable detection means may be employed to detect relevant informationabout the autonomic nervous system.

In certain embodiments, a control feedback loop is provided. Forexample, during or following a particular treatment regimen, thesympathetic activity and/or parasympathetic activity may be monitored,observed, detected, etc., e.g., by sensing conduction in at least aportion of the sympathetic system and/or parasympathetic system by anysuitable method. Other methods that may be employed to monitor theautonomic system include, but are not limited to, amounts of T helpercells (Th1 and/or Th2), neurography, continuous or serial measurementsof circulating catecholamine levels, chronotropic, inotropic, andvasodilator responses, heart rate variability (“HRV”), particularhormonal levels, e.g., associated with a particular phase of themenstrual cycle, post-ganglionic action potentials, QT interval, and thelike. For example, in certain embodiments HRV measures such as lowfrequency peak (“LF”), high frequency peak (“HF”), and the LF/HF ratiomay be used to monitor the autonomic nervous system, as well as, but notlimited to, plasma volume, effective renal plasma volume, effectiverenal blood flow, norepinephrine, and concentrations ofrennin-angiotensin-aldosterone system hormones. For example, a sensorsuitable for detecting nerve cell or axon activity that are related tothe autonomic nervous system may be implanted in a portion of asubject's body. A sensor may take the form of an electrode or the like.Signals received by such a sensor may be amplified before furtherprocessing. A sensor may also take the form of a device capable ofdetecting nerve compound action potentials or may take the form of atransducer that includes an electrode with an ion selective coatingapplied which is capable of directly transducing the amount of aparticular transmitter substance or its breakdown by-products.

Embodiments include utilizing a feedback system in such a manner that,if the desired increase/decrease in sympathetic and/or parasympatheticactivity is not achieved, the same or a different treatment protocol formodulating the activity of the autonomic nervous system activity may beperformed. For example, in those instances where a different modulationprotocol is performed from a first modulation protocol, one or more ofthe treatment parameters may be modified. For example, if a firstmodulation protocol included pharmacological modulation, a second,different modulation protocol may be employed, e.g., a differentpharmacological agent may be employed instead or in addition to thefirst, where the differences may include dosage, type, mode ofadministration, etc., or the second protocol may include an electricalmodulation protocol. In those instances where a different protocol isperformed from a first, electrical energy modulation protocol, one ormore of the treatment parameters may be modified for a second, differentelectrical modulation protocol, e.g., a different electrical energyprotocol may be employed instead of or in addition to the first, wherethe differences may include voltage, frequency, pulse width, etc., orthe second protocol may include a pharmacological modulation protocol.

Certain embodiments may include simultaneously monitoring, detecting,observing, etc., (i.e., in “real time”) the sympathetic activity and/orparasympathetic activity such that modulation of at least a portion ofthe autonomic nervous system may be performed to treat a condition andthe result of the modulation may be observed and/or monitored, e.g., atleast once, continuously or intermittently or periodically and incertain embodiments until the desired increase or inhibition in activityis observed or longer. Still further, in many embodiments once thedesired autonomic nervous system modulation is achieved the same ordifferent modulation treatment protocol may be performed thereafter atleast one time and may be for a period of time, e.g., one or more times,to maintain the desired state such that embodiments of the subjectmethods may be repeated one or more times.

The above-described methods find use in a variety of differentapplications, representative types of which are described in greaterdetail below.

Utility

The subject methods find use in a variety of applications in which it isdesired to treat a subject for a condition at least suspected of beingexacerbated during at least one menstrual cycle phase. Such conditionsmay be referred to as conditions that have catamenial variations. Inaccordance with embodiments of the subject invention, at least a portionof a subject's autonomic nervous system is modulated to increase theparasympathetic activity/sympathetic activity ratio in a mannersufficient to treat the subject for the condition. In accordance withembodiments of the subject invention, at least a portion of a subject'sautonomic nervous system is modulated to decrease the parasympatheticactivity/sympathetic activity ratio in a manner sufficient to treat thesubject for the condition.

The subject methods find use in the treatment of a variety of differentconditions, including, but not limited to, cardiovascular conditionsincluding cardiovascular disease, e.g., atherosclerosis, coronary arterydisease, hypertension, hyperlipidemia, eclampsia, pre-eclampsia,cardiomyopathy, volume retention, congestive heart failure, QT intervalprolongation, aortic dissection, aortic aneurysm, arterial aneurysm,arterial vasospasm, myocardial infarction, reperfusion syndrome,ischemia, sudden adult death syndrome, arrhythmia, fatal arrythmias,coronary syndromes, coronary vasospasm, sick sinus syndrome,bradycardia, tachycardia, thromboembolic disease, deep vein thrombosis,coagulopathy, disseminated intravascular coagulation (“DIC”), mesentericischemia, syncope, venous thrombosis, arterial thrombosis, malignanthypertension, secondary hypertension, primary pulmonary hypertension,secondary pulmonary hypertension, raynaud's, paroxysmal supraventriculartachycardia, and the like; neurodegenerative conditions includingneurodegenerative diseases, e.g., Alzheimer's Disease, Pick's Disease,Parkinson's Disease, dementia, delirium, amyotrophic lateral sclerosis,and the like; neuroinflammatory conditions including neuroinflammatorydiseases, e.g., viral meningitis, viral encephalitis, fungal meningitis,fungal encephalitis, multiple sclerosis, charcot joint, schizophrenia,myasthenia gravis, and the like; orthopedic inflammatory conditionsincluding orthopedic inflammatory diseases, e.g., osteoarthritis,inflammatory arthritis, regional idiopathic osteoporosis, reflexsympathetic dystrophy, Paget's disease, osteoporosis, antigen-inducedarthritis, juvenile chronic arthritis, and the like; lymphoproliferativeconditions including lymphoproliferative diseases, e.g., lymphoma,lymphoproliferative disease, Hodgkin's disease, inflammatory pseudomotorof the liver, and the like; autoimmune conditions including autoimmunediseases, e.g., Graves disease, raynaud's, hashimoto's, takayasu'sdisease, kawasaki's diseases, arteritis, scleroderma, CREST syndrome,allergies, dermatitis, Henoch-schlonlein purpura, goodpasture syndrome,autoimmune thyroiditis, myasthenia gravis, Reiter's disease, lupus, andthe like; inflammatory conditions, e.g., acute respiratory distresssyndrome (“ARDS”), multiple sclerosis, rheumatoid arthritis, juvenilerheumatoid arthritis, juvenile chronic arthritis, migraines, chronicheadaches, and the like; infectious diseases, e.g., sepsis, viral andfungal infections, diseases of wound healing, wound healing,tuberculosis, infection, AIDS, human immunodeficiency virus, and thelike; pulmonary conditions including pulmonary diseases, e.g.,tachypnea, fibrotic lung diseases such as cystic fibrosis and the like,interstitial lung disease, desquamative interstitial pneumonitis,non-specific interstitial pneumonitis, lymphocytic interstitialpneumonitis, usual interstitial pneumonitis, idiopathic pulmonaryfibrosis, pulmonary edema, aspiration, asphyxiation, pneumothorax,right-to-left shunts, left-to-right shunts, respiratory failure, and thelike; transplant-related conditions such as transplant related sideeffects such as transplant rejection, transplant-related tachycardia,transplant related renal failure, transplant related bowel dysmotility,transplant-related hyperreninemia, and the like; gastrointestinalconditions including gastrointestinal diseases, e.g., hepatitis,xerostomia, bowel mobility, peptic ulcer disease, constipation, ileus,irritable bowel syndrome, post-operative bowel dysmotility, inflammatorybowel disease, typhilitis, cholelithiasis, cholestasis, fecalincontinence, cyclic vomiting syndrome, and the like; endocrineconditions including endocrine diseases, e.g., hypothyroidism,hyperglycemia, diabetes, obesity, syndrome X, insulin resistance,polycystic ovarian syndrome (“PCOS”), and the like; genitourinaryconditions including genitourinary diseases, e.g., bladder dysfunction,renal failure, hyperreninemia, hepatorenal syndrome, pulmonary renalsyndrome, incontinence, arousal disorder, menopausal mood disorder,premenstrual mood disorder, renal tubular acidosis, pulmonary renalsyndrome, and the like; skin conditions including skin diseases, e.g.,wrinkles, cutaneous vasculitis, psoriasis, and the like; agingassociated conditions including aging associated diseases, e.g., shydragers, multi-system atrophy, age related inflammation conditions,cancer, aging, and the like; neurologic conditions including neurologicdiseases such as epilepsy, depression, schizophrenia, seizures, stroke,insomnia, cerebral vascular accident, transient ischemic attacks,stress, bipolar disorder, concussions, post-concussive syndrome,cerebral vascular vasospasm, central sleep apnea, obstructive sleepapnea, sleep disorders, headaches including chronic headaches,migraines, acute disseminated encephalomyelitis (“ADEM”), and the like;Th-2 dominant conditions including Th-2 dominant diseases, e.g.,typhilitis, osteoporosis, lymphoma, myasthenia gravis, lupus, and thelike; conditions, including diseases, that cause hypoxia, hypercarbia,hypercapnia, acidosis, acidemia, e.g., ventilation/perfusion (V/Q)mismatch, Chronic Obstructive Pulmonary Disease (“COPD”), emphysema, anychronic lung disease that causes acidosis, acute pulmonary embolism,sudden adult death syndrome (“SADS”), chronic pulmonary embolism,pleural effusion, cardiogenic pulmonary edema, non-cardiogenic pulmonaryedema, acute respiratory distress syndrome (ARDS), neurogenic edema,hypercapnia, acidemia, asthma, renal tubular, asthma, acidosis, chroniclung diseases that cause hypoxia, hypercarbia or hypercapnia, and thelike; OB-GYN conditions including OB-GYN diseases, e.g., amniotic fluidembolism, menopausal mood disorders, premenstrual mood disorders,pregnancy-related arrhythmias, fetal stress syndrome, fetal hypoxia,amniotic fluid embolism, gestational diabetes, pre-term labor, cervicalincompetence, fetal distress, peri-partum maternal mortality, peripartumcardiomyopathy, labor complications, premenstrual syndrome,dysmenorrheal, endometriosis, fertility and subfertility conditions suchas infertility, early pregnancy loss, spontaneous abortion,subfertility, failure of implantation, amenorrhea, luteal insufficiency,and the like; sudden death syndromes, e.g., sudden adult death syndrome,and the like; menstrual related disorders, e.g., pelvic pain,dysmenorrheal, gastrointestinal disease, nausea, and the like;peripartum and pregnancy related conditions, e.g., peripartumcardiomyopathy, and the like; fibrosis; post-operative recoveryconditions such as post-operative pain, post operative ileus,post-operative fever, post-operative nausea, and the like;post-procedural recovery conditions such as post-procedural pain, postprocedural ileus, post-procedural fever, post-procedural nausea, and thelike; chronic pain; trauma; hospitalization; glaucoma; disorders ofthermoregulation; fibromyalgia; and the like. Other conditions may alsobe treated in accordance with the subject invention. Embodiments of thesubject invention include treating one or more conditions, sequentiallyor at the same time, in accordance with the subject invention.

By “treatment” is meant that at least an amelioration of the symptomsassociated with the condition afflicting the subject is achieved, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g., symptom, associated with thecondition being treated. As such, treatment also includes situationswhere the condition, or at least symptoms associated therewith, arecompletely inhibited, e.g., prevented from happening, or stopped, e.g.terminated, such that the subject no longer suffers from the condition,or at least the symptoms that characterize the condition.

A variety of subjects are treatable according to the subject methods. Inmany embodiments the subjects are “mammals” or “mammalian”, where theseterms are used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In many embodiments, the subjects are humansand particularly female humans. While the present invention may be usedfor the treatment of a human, female subject, it is to be understoodthat the subject methods may also be carried-out on other female animalsubjects such as, but not limited to, mice, rats, dogs, cats, livestockand horses, etc. Accordingly, it is to be understood that any femalesubject in need of being treated according to the subject invention issuitable.

Moreover, suitable subjects of this invention include those who have andthose who have not previously been afflicted with a condition, thosethat have previously been determined to be at risk of suffering from acondition, and those who have been initially diagnosed or identified asbeing afflicted with or experiencing a condition.

Devices and Systems

The subject invention also includes devices and systems that may beemployed in the practice of the subject methods. The subject systems mayinclude an effective amount of at least pharmacological agent. Thepharmacological agent may be in any suitable formulation or form. Forexample, a system may include a pharmacological composition fortransdermal administration, e.g., present as an active agent of atransdermal patch, film or the like, an oral dosage form, injectiondosage form, suppository, etc.

In certain embodiments, the subject systems may also include suitablepharmacological agent delivery means, the particulars of which may bedictated by the particular pharmacological agent employed, e.g., theparticular form of the agent such as whether the pharmacological agentis formulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants and aerosols, and thelike, and the particular mode of administration of the agent, e.g.,whether oral, buccal, rectal, parenteral, intraperiactivityal,intradermal, transdermal, intratracheal, intravaginal, endocervical,intrathecal, intranasal, intravesicular, on the eye, in the ear canal,etc. Accordingly, certain systems may include a suitable drug deliverydevice, e.g., a suppository applicator, syringe, I.V. bag and tubing,electrode, an implantable drug delivery device, an electrostimulatorydevice, and the like.

Systems may also include one or more devices for delivering, e.g.,implanting, a component such as a drug delivery device, anelectrosurgical device, and the like, to a target site of a subject suchas into the body cavity of a subject. For example, an endoscope,introducer needle, and the like, may be provided. Systems may alsoinclude one or more imaging or scanning apparatuses such as afluoroscope, CT scan, and the like.

Embodiments of the subject systems may also include an electrical energysupplying device such that a system according to the present inventionmay include at least one electrode for electrically modulating at leasta portion of a subject's autonomic nervous system. In certainembodiments the electrical energy supplying device may be an implantabledevice, or at least certain components such as one or more electrodes,may be implantable. Certain embodiments may include a plurality ofelectrodes, where some or all may be the same or some or all may bedifferent. For example, at least a first electrode may be provide forelectrically stimulating at least a portion of the autonomic nervoussystem and at least a second electrode may be provided for inhibitingactivity in at least a portion of the autonomic nervous system. Incertain embodiments, a “test” electrode, as described above, may beincluded in a system. As noted above, such “test” electrodes may be aradiofrequency controlled electrode. Still further, one or moreelectrodes may be included in a system which, instead of or in additionto delivering electric impulses to at least a portion of the autonomicnervous system, delivers an autonomic nervous system pharmacologicalagent to at least a portion of the autonomic nervous system, e.g., maybe used to deliver a pharmacological agent. Included may be an energysource such as a battery or generator, where in certain embodiments theenergy source may be implantable, and may also include one or more leadsor wires for coupling the one or more electrodes to an energy source.

A system for use in practicing the subject methods may also include asuitable detector for detecting one or more physical and/or chemicalaspects related to the autonomic nervous system. The detector at leastincludes data gathering means. Also provided may be data analysis meanswhere such may be a separate component from or integral with datagathering means, but in many embodiments is operatively coupled to datagathering means, e.g., integral with. In use, data related to one ormore aspects of the autonomic nervous system may be collected by datagathering means and forwarded to data analysis means which executessteps necessary to process and evaluate the collected data and determinewhether at least a portion of the autonomic nervous system is in need ofmodulation. Such evaluation may include comparing data to referencevalues, etc. For example, reference values may represent normalparasympathetic activity/sympathetic activity ratios, as describedabove, such as parasympathetic activity/sympathetic activity ratios ofhealthy, like women in a particular menstrual cycle phase and/orparasympathetic activity/sympathetic activity ratios of the subjectduring a particular menstrual cycle phase, typically one in which thecondition of interest is not exacerbated or, if the phase is the samephase in which the condition is observed to be exacerbated, there is noobservable exacerbation at the time the ratio is observed for use as areference data point.

When present, a detector (or data evaluation means if separate) may beoperatively coupled to one or more other elements of a given drugdelivery means and/or electrical energy supplying device such thatresults of the determinations of autonomic modulation may automaticallytrigger (or cease) activation of drug delivery and/or electrical energyto the autonomic nervous system. Suitable detectors include any detectorcapable of gathering information about the autonomic nervous system andincludes both invasive, minimally invasive and non-invasive detectorswhere in certain embodiments a detector may be an implantable detector.Suitable detectors include, but are not limited to, those capable ofcollecting data regarding nerve conduction, circulating catecholaminelevels, heart rate variability (“HRV”), respiratory sinus arrhythmia,post-ganglionic action potentials, QT interval, and the like andinclude, but are not limited to, MRI apparatuses, CT apparatus, hormonelevel detectors, neurography apparatuses, cardiovascular monitors,sensors including electrodes, etc.

Computer Readable Mediums and Programming Stored Thereon

Any part of the subject methods, e.g., detection, analysis andactivation/termination of drug delivery and/or electrical energyincluding selecting suitable drug delivery parameters and/or electricalparameters, may be performed manually or automatically. For example, thesubject invention may include suitable computing means such as suitablehardware/software for performing one or more aspects of the subjectmethods. For example, one or more aspects of the subject invention maybe in the form of computer readable media having programming storedthereon for implementing the subject methods. Accordingly, programmingaccording to the subject invention may be recorded on computer-readablemedia, e.g., any medium that can be read and accessed directly orindirectly by a computer. Such media include, but are not limited to,computer disk or CD, a floppy disc, a magnetic “hard card”, a server,magnetic tape, optical storage such as CD-ROM and DVD, electricalstorage media such as RAM and ROM, and the hybrids of these categoriessuch as magnetic/optical storage media. One of skill in the art canreadily appreciate how any of the presently known computer readablemediums may be used to provide a manufacture that includes a recordingof the present programming/algorithm for carrying out theabove-described methodology. Thus, the computer readable media may be,for example, in the form of any of the above-described media or anyother computer readable media capable of containing programming, storedelectronically, magnetically, optically or by other means. As such,stored programming embodying steps for carrying-out some or all of thesubject methods may be transferred to a computer-operated apparatus suchas a personal computer (PC) or the like, by physical transfer of a CD,floppy disk, or like medium, or may be transferred using a computernetwork, server, or other interface connection, e.g., the Internet.

For example, the subject invention may include a computer readablemedium that includes stored programming embodying an algorithm forcarrying out some or all of the subject methods, where such an algorithmis used to direct a processor or series of processors to execute thesteps necessary to perform the task(s) required of it and as such incertain embodiments the subject invention includes a computer-basedsystem for carrying-out some or all of the subject methods. For example,such a stored algorithm may be configured to, or otherwise be capableof, directing a microprocessor to receive information directly orindirectly from data gathering means (i.e., information collected bydata gathering means about the autonomic nervous system) and processthat information to determine the state of the autonomic nervous system,e.g., the activity level of the parasympathetic system and/or thesympathetic system and even whether the autonomic nervous systemrequires modulation and, if so, the specifics of the modulation that maybe required, e.g., to treat a condition. The result of that processingmay be communicated to a user, e.g., via audio and/or visual means,e.g., the algorithm may also include steps or functions for generating avariety of autonomic nervous system profile graphs, plots, etc.

The algorithm may be configured to, or otherwise be capable of,directing a microprocessor to activate, i.e., turn “on” and “off” a drugdelivery device, e.g., an implantable or external drug delivery deviceand/or an electrical energy supplying device for applying energy to atleast a part of the autonomic nervous system, e.g., in response to theabove-described determination of the state of the autonomic nervoussystem. For example, if it is determined that sympathetic and/orparasympathetic activity needs to be increased or decreased, theprocessor may direct a drug delivery device to provide the appropriateamount of drug or otherwise execute a suitable drug treatment regime toresult in the desired action. Likewise, in embodiments employingelectrical modulation, if it is determined that sympathetic and/orparasympathetic activity needs to be increased or decreased, theprocessor may direct an electrical energy supplying device to providethe appropriate electric impulse or otherwise execute a suitableelectric energy treatment regime to result in the desired action

The subject invention may also include a data set of known or referenceinformation stored on a computer readable medium to which autonomicnervous system data collected may be compared for use in determining thestate of the autonomic nervous system. The data may be stored orconfigured in a variety of arrangements known to those of skill in theart.

Kits

Also provided are kits for practicing the subject methods. The subjectkits may vary greatly in regards to the components included. Embodimentsmay include one or more pharmacological agents and/or electrical energysupplying devices. In those embodiments that include one or morepharmacological agents, the amount of the pharmacological agentsprovided in a kit may be sufficient for a single application or formultiple applications. Accordingly, in certain embodiments of thesubject kits a single dosage unit of at least one pharmacological agentmay be present for a single application.

In certain other embodiments, multiple dosage units of one or morepharmacological agents may be present in a kit for multipleapplications. In those embodiments having multiple dosage units, suchmay be packaged in a single container, e.g., a single tube, bottle,vial, and the like, or one or more dosage units may be individuallypackaged such that certain kits may have more than one container of apharmacological agent or of different pharmacological agents.

A kit may include a monthly pack that includes daily discrete orcontinuous unit doses wherein the total number of daily units present inthe monthly pack and may be equal to the total number of days of a monthor the days of the menstrual cycle, e.g., a monthly pack may include aminimum of about 30 to about 90 days, e.g., about 30 to about 84 days.The pack may include, for example daily unit doses in the form of oraldosage forms such as tablets, capsules and the like. The monthly packmay be a two or more stage pharmaceutical pack, e.g., containing atleast about 30 daily unit doses in two stages. In its first stage, sucha pack may include a first pharmaceutical agent or placebo, wherein thefirst stage includes a minimum of about 25 and a maximum of about 77daily discrete or continuous doses, e.g., equal to the number of days ofone or more particular menstrual cycle phases. The second stage mayinclude a second pharmaceutical agent equal to the number of days of oneor more particular menstrual cycle phases (e.g., the luteal phase and/ormenses phase), e.g., 5, 6 or 7 daily discrete or continuous unit doses.The first and second pharmaceutical agents may differ in one or morerespects, e.g., they may be different pharmaceutical agents (differenttypes), they may be the same pharmaceutical agent but may differ in doseof active agent, etc. More stages may be included in certainembodiments. Accordingly, the monthly pack may include a number of pillsto be administered by a subject each day of the month or of themenstrual cycle wherein the pack is configured to include certain pillsto be administered to a subject on certain days or during certainmenstrual cycle phases, where the type, dosage, etc. of the pills of thepack may vary.

Suitable means for delivering one or more pharmacological agents to asubject may also be provided in a subject kit. The particular deliverymeans provided in a kit may be dictated by the particularpharmacological agent employed, as describe above, e.g., the particularform of the agent such as whether the pharmacological agent isformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants and aerosols, and thelike, and the particular mode of administration of the agent, e.g.,whether oral, buccal, rectal, parenteral, intravaginal, endocervical,intrathecal, intranasal, intravesicular, on the eye, in the ear canal,intraperiactivityal, intradermal, transdermal, intratracheal, etc.Accordingly, certain systems may include a suppository applicator,syringe, I.V. bag and tubing, electrode, transdermal patch or film, etc.

Kits may also include diagnostic or detection tests, for detecting theoccurrence or onset of a particular phase of a subject's menstrualcycle, e.g., by determining certain hormone levels, including relativehormone levels. For example, a urine leutinizing hormone (“LH”)detection test or kit or the like may be present in a kit, where suchurine LH detection kits are known in the art, e.g., OVUQUICK ONE-STEP,CLEARPLAN EASY and SURESTEP brand detection tests.

Kits may include an electrical energy supplying device, as describedabove. Accordingly, subject kits may include an energy supplying devicesuch that they may include at least one electrode for electricallymodifying at least a portion of a subject's autonomic nervous system inaccordance with the subject invention, as described above. In certainembodiments, the energy supplying device provided in a kit is animplantable device, or at least certain components such as one or moreelectrodes, may be implantable. Certain kits may include a plurality ofelectrodes, where some or all may be the same or some or all may bedifferent. For example, certain kits may include at least a firstelectrode for electrically modulating activity at least a portion of thesympathetic system and at least a second electrode for electricallymodulating activity in at least a portion of the parasympathetic system.In certain embodiments, a subject kit may include a “test” electrode, asdescribed above such as a radiofrequency controlled electrode. Stillfurther, one or more electrodes may be included in a kit which, insteadof or in addition to delivering electric impulses to at least a portionof the autonomic nervous system, delivers an autonomic nervous systempharmacological agent to at least a portion of the autonomic nervoussystem. Kits according to the subject invention typically also includean energy source such as a battery or generator, where in certainembodiments the energy source may be implantable, and may also includeone or more leads or wires for coupling the one or more electrodes to anenergy source.

Devices for delivering, e.g., implanting, an electrical energy supplyingdevice and/or a drug delivery device to a target site of a subject suchas into the body cavity of a subject may also be included in the subjectkits. For example, an endoscope, introducer needle, and the like may beprovided.

The subject kits may also include instructions for how to practice thesubject methods. For example, instructions may include how to administerthe one or more pharmaceutical agents provided in the kit to treat asubject for a condition by pharmacologically modulating at least aportion of the subject's autonomic nervous system. Instructions mayinclude how to use an energy supplying device provided in the kit totreat a subject for a condition by electrically modulating at least aportion of the subject's autonomic nervous system. The instructions aregenerally recorded on a suitable recording medium or substrate. Forexample, the instructions may be printed on a substrate, such as paperor plastic, etc. As such, the instructions may be present in the kits asa package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging orsub-packaging) etc. In other embodiments, the instructions are presentas an electronic storage data file present on a suitable computerreadable storage medium, e.g. CD-ROM, diskette, etc. In yet otherembodiments, the actual instructions are not present in the kit, butmeans for obtaining the instructions from a remote source, e.g. via theinterne, are provided. An example of this embodiment is a kit thatincludes a web address where the instructions can be viewed and/or fromwhich the instructions can be downloaded. As with the instructions, thismeans for obtaining the instructions is recorded on a suitablesubstrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is evident from the above discussion that the above describedinvention provides methods, system and kits for treating a subject for acondition that is at least suspected of being exacerbated during one ormore menstrual cycle phases, e.g., a condition that has catamenialvariations. As such, the subject invention represents a significantcontribution to the art.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1.-68. (canceled)
 69. A multi-dose package comprising: a first unitdosage of an active agent and a second unit dosage of the active agent;wherein the amount of the active agent in the first unit dosage differsfrom the amount of the active agent in the second unit dosage, andwherein the unit dosages of the active agent are selected to treat asubject for a condition that is increased in severity or occurrenceduring one or more phases of the menstrual cycle.
 70. The multi-dosepackage according to claim 69, wherein the multi-dose package is in theform of a monthly package.
 71. The multi-dose package according to claim69, wherein the multi-dose package is in the form of a seasonal package.72. The multi-dose package according to claim 69, wherein the multi-dosepackage is in the form of a yearly package.
 73. The multi-dose packageaccording to claim 69, wherein the package further comprises a placebo.74. The multi-dose package according to claim 69, wherein the unitdosages are configured for oral administration.
 75. The multi-dosepackage according to claim 69, wherein the package further comprises asecond active agent.
 76. The multi-dose package according to claim 69,wherein the unit dosages of the second active agent are selected totreat a subject for a second condition that is increased in severity oroccurrence during one or more phases of the menstrual cycle.
 77. Themulti-dose package according to claim 69, wherein the package istailored for a particular subject.
 78. The multi-dose package accordingto claim 69, wherein the condition is chosen from cardiovascularconditions; neurodegenerative conditions; neuroinflammatory conditions;orthopedic inflammatory conditions; lymphoproliferative conditions;autoimmune; inflammatory conditions; infectious diseases; pulmonaryconditions; transplant-related conditions; gastrointestinal conditions;endocrine conditions; genitourinary conditions; skin conditions;aging-associated conditions; neurologic conditions; Th-2 dominantconditions; conditions that cause hypoxia; conditions that causehypercarbia; conditions that cause hypercapnia; conditions that causeacidosis; conditions that cause acidemia; OB-GYN conditions; suddendeath syndromes; peripartum and pregnancy related disorders; fibrosis;post-operative recovery conditions; post-procedural recovery conditions;chronic pain; trauma; bacterial infections; and fibromyalgia.
 79. Themulti-dose package according to claim 69, wherein the active agent ischosen from: statins; beta-blockers; diuretics; calcium channelblockers; angiotensin converting enzyme (ACE) inhibitors; beta agonists;antihistamines; steroids; anticoagulants; and diabetes agents.
 80. Themulti-dose package according to claim 69, wherein the active agent is astatin.
 81. The multi-dose package according to claim 69, wherein theactive agent is a beta-blocker.
 82. The multi-dose package according toclaim 69, wherein the active agent is a diuretic.
 83. The multi-dosepackage according to claim 69, wherein the active agent is a calciumchannel blocker.
 84. The multi-dose package according to claim 69,wherein the active agent is an angiotensin converting enzyme (ACE)inhibitor.
 85. The multi-dose package according to claim 69, wherein theactive agent is a beta agonist.
 86. The multi-dose package according toclaim 69, wherein the active agent is an anti-histamine.
 87. Themulti-dose package according to claim 69, wherein the active agent is asteroid.
 88. The multi-dose package according to claim 69, wherein theactive agent is an anticoagulant.
 89. The multi-dose package accordingto claim 69, wherein the active agent is a diabetes agent.
 90. A methodof treating a subject for a condition that is increased in severity oroccurrence during one or more phases of the menstrual cycle, the methodcomprising: administering to a subject one of a plurality of unit dosageforms of an active agent contained in a single multi-dose packagecomprising: a first unit dosage of an active agent and a second unitdosage of the active agent; wherein the amount of the active agent inthe first unit dosage differs from the amount of the active agent in thesecond unit dosage, and wherein the unit dosages of the active agent areselected to treat a subject for a condition that is increased inseverity or occurrence during one or more phases of the menstrual cycle.